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MXPA02007249A - Integrin expression inhibitors. - Google Patents

Integrin expression inhibitors.

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Publication number
MXPA02007249A
MXPA02007249A MXPA02007249A MXPA02007249A MXPA02007249A MX PA02007249 A MXPA02007249 A MX PA02007249A MX PA02007249 A MXPA02007249 A MX PA02007249A MX PA02007249 A MXPA02007249 A MX PA02007249A MX PA02007249 A MXPA02007249 A MX PA02007249A
Authority
MX
Mexico
Prior art keywords
group
produssion
mmol
ppm
ring
Prior art date
Application number
MXPA02007249A
Other languages
Spanish (es)
Inventor
Toru Haneda
Original Assignee
Eisai Co Ltd
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Filing date
Publication date
Application filed by Eisai Co Ltd filed Critical Eisai Co Ltd
Publication of MXPA02007249A publication Critical patent/MXPA02007249A/en

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

Integrin expression inhibitors and remedies for arteriosclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinitis or inflammatory diseases, anticoagulant agents and cancerous metastasis inhibitors based on the integrin inhibitory effect. Namely, integrin expression inhibitors containing as the active ingredient sulfonamide compounds represented by the following general formula (I), pharmacologically acceptable salts thereof or hydrates of the same wherein B represents optionally substituted C6 10 aryl or 6 to 10 membered heteroaryl wherein the ring may be partly saturated; K represents a single bond, CH=CH or (CR4bR5b)mb (wherein R4b and R5b may be the same or different and each represents hydrogen or C1 4 alkyl; and mb represents an integer of 1 or 2); R1 represents hydrogen or C1 6 alkyl; Z represents a single bond or CO NH ; and R represents optionally substituted C6 10 aryl or 6 to 10 membered heteroaryl wherein the ring may be partly saturated.

Description

Inhibitor of integrin expression Technical Field The present invention relates to an inhibitor of the integrin expression, specifically, to an inhibited one, of the expression of an integrin a2ßl, a3ßl, a5ßl, adßl, avßl, avß3 or avß5. It also refers to an angiogenesis agent, an anticoagulant, an anticancer agent, a suppressor of cancer metastases, and an agent for the treatment of retinal angiogenesis, diabetic retinopathy, inflammatory diseases, arterial sclerosis, psoriasis and osteoporosis, in based on the inhibitory action of integrin expression. Prior art Integrin consists structurally of a heterodimer in which two types of subunits are associated, namely integrin a and integrin β, with one another by a non-covalent bond. At least 16 types of chains a and 8 types of ß chains have been found. A variety of molecular groups are formed that differ in the specificity of the li-gand by the combination of these α and β chains and 22 types of integrins are known. The integrin has a function as a receptor protein of the cell membrane for an adhesion molecule of the animal cells, which is expressed on a cell membrane and participates in the adhesion between a cell and an extracellular matrix (ECM) or between cells. When the adhesion molecule to the cell is combined with the integrin, a signaling system in a cell initiates the movement and as a result not only adhesion to the cell works, but also cell evolution, cell proliferation, apoptosis , differentiation, cytoskeletal orientation, cell migration, histogenesis, cancer infiltration and metastasis, wound healing, blood coagulation and the like. It is known that among these integrins, the a2ßl integrin whose adhesion molecules are collagen and laminin participates in platelet aggregation, cancer infiltration and metastasis (HAYASHI Masao &MIYAMOTO Yasunori, PROTEIN, NUCLEIC ACID, ENZYME, Vol 44, ppl30-135, (1999)) in angiogenesis (Donald R. Senger et al, Proc. Nati, Acad. Sci. USA, 94, 13612-13617, (1997)). This has come to clarify that among these symptoms, the proliferation of cancer is closely related to angiogenesis. In recent years, it has been experimentally demonstrated that an angiogenesis agent can inhibit and further reduce proliferative cancer and a resistant cancer is not generated in a cancer transplant model and a correlation has been shown between angiogenesis and the exacerbations of many cancers solids such as breast cancer, prostate cancer, lung cancer and colon cancer in clinical examinations (T. Boem et al, Nature, 390 (27) 404-407, (1997)). In addition, avßl whose adhesion molecules are fibronectin and vitronectin participates in the adhesion to a cancer cell in a substrate and avß3 whose adhesion molecules are vitronectin and tro-boespongine and avß5 whose adhesion molecule is vitronectin involved in angiogenesis, cancer metastasis and bone regeneration (Shattil, SJ, Thromb Haemost, 74, 149-155, (1995), Friedlander M, et al, Sceience, 270, 1500-1502, (1995 )). Furthermore, it is known that the a3ßl whose adhesion molecules are fibronectin, collagen, laminin, lammine 5 and the like, the a5ßl whose adhesion molecule is fibronectin and a6ßl whose adhesion molecules are laminin and laminin 5 they participate in the infiltration of cancer and in metastasis (MATSUURA Nariaki et al., JAPAN CLINIC, Vol 53, ppl643-1647, (1995), OTA Ichiro et al, CLINICAL PATHOLOGY, Vol 45, 528-533, (1997)) . WO9950249 describes the avß3 integrin antagonist, however it makes no suggestion regarding the . . ?.,., ^. "A. JA .... ^^ jjj. ^^^ 1 ^ inhibitory action of the expression of integrin avß3. In JP-A 7-165708 and JP-A 8-231505, the same sulfonamide compound as used in the present invention is disclosed.; however, there is no description or indication regarding the inhibitory action of integrin expression. O9301182 describes antitumor agents using a tyrosine kinase inhibitory action specific to a compound having an indole backbone. These agents are indolylmethylene-2-indolinone compounds which differ from those of the present invention. O964016 also describes antitumor agents that utilize a tyrosine kinase inhibitory action specific to a compound having an indole backbone. However, these agents are 2-indolinone-3-methylene derivatives which differ from those of the present invention. Heretofore has not been known of an antiangiogenesis agent, an anticancer agent, a suppressor of cancer metastasis, an anticoagulant agent, and an agent for the treatment of arterial sclerosis, psoriasis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases based on Inhibitory action of integrin expression. The present invention provides an agent for the treatment of a disease against which an inhibitory action of integrin expression is effective. Specifically, it is an object of the present invention to provide an anti-angiogenic agent, an anti-cancer agent, a cancer metastasis suppressant, an anticoagulant, and an agent for the treatment of arterial sclerosis, psoriasis, osteoporosis, retinal angiogenesis, Diabetic retinopathy or inflammatory diseases, comprising, as an active ingredient, a compound that has an inhibitory action of integrin expression. Another object of the present invention is to provide an inhibitor of the expression . , ... p5yfoft «Aj ~, f k .... ^ t«. Integrin ion comprising a sulfonamide compound. Description of the Invention The present inventors have conducted serious studies and as a result, found that a sulfonamide compound having a bicyclic heterocycle has an inhibitory action of integrin expression. Thus, they have completed the present invention. Accordingly, the present invention relates to: 1. l) an agent for the treatment of arthral sclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant , 3) a suppressor of cancer metastasis or 4) an antiangiogenic agent based on an inhibitory action of the expression of an inte-grin, 2. 1) the agent for the treatment of arterial sclerosis, psoriasis, cancer, osteoporosis, retinal agiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant, 3) a suppressor of cancer metastasis or 4) an antiangiogenic agent based on an inhibitory action of the expression of a integrin as described in 1., where the integrin is an integrin a2, a3, a5, a6, av, ßl, ß3, ß4, ß5, a2ßl, a3ßl, a5ßl, a6ßl, avßl, avß3 or avß5, 3. an inhibitor of the expression of an integrin comprise and, as an active ingredient, a sulfonamide compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate thereof: B-K-S02N- -Z7 - RR (O (in the formula, B represents a C6-C10 aryl ring or a 6 to 10-membered heteroaryl ring which may have a _gj_í_i ____! _ iia J aá ??? tk .j Má3t * Ab. substituent and a part of the ring may be saturated; K represents a single bond, -CH = CH- or - (CR4bR5b) mb- (where R4b and R5b are the same or different from each other and each represents a hydrogen atom or a C1-C4 alkyl group, and tn means a whole between 1 and 2); R1 represents a hydrogen atom or a C1-C6 alkyl group; Z represents a single bond or -CO-NH-; and R represents a C6-C10 aryl ring or a 6 to 10 membered heteroaryl ring which may have a substituent and a part of the ring may be saturated, respectively), 4. an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound described in 3., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein R is indole, quinoline or isoquinoline, 5. an inhibitor of the integrin expression comprising, as a active ingredient, a sulfonamide compound represented by the formula (Ia), a pharmacologically acceptable salt thereof or a hydrate thereof: (in the formula, the ring Aa a monocyclic or bicyclic aromatic ring which may have a substituent, the ring Ba represents an optionally substituted 6-membered unsaturated cyclic hydrocarbon or a 6-membered unsaturated heterocycle containing a nitrogen atom as a hetero atom the Ca ring represents an optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atoms; r. { ^^^^ t M represents a hydrogen atom or a C1-C6 alkyl group; Wa represents a single bond or -CH = CH -, - Ya represents a carbon atom or a nitrogen atom; and Za represents - N (R2a) - (where R2a signifies a hydrogen atom or a lower alkyl group) or a nitrogen atom, respectively), 6. an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound as described in 5., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein a is a single bond, an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound described in 5., a pharmacologically acceptable salt thereof or a hydrate thereof, where a is a single bond; Za is -NH-, - and is already a carbon atom8. The inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound as described in any of 5., 6. and 7., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein ring Ba is an optionally substituted benzene or pyridine, 9. an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound as described in any of 5. to 8., a pharmacologically acceptable salt thereof. or a hydrate thereof, wherein ring C is an optionally substituted pyrrole, an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound described in 5., a pharmacologically acceptable salt of the same or a hydrate of them, where the ring Aa is a benzene or pyridine which may have a substituent; Ring Ba is benzene which may have a substituent; the Ca ring is pyrrole which may have a substituent; Wa is a simple link; and Za is -NH-, 11. an inhibitor of integrin expression comprising, as an active ingredient, a heterocyclic compound containing sulfonamide represented by the formula (Ib), a farra- cologically acceptable of it or a hydrate of them OR (in the formula, Ab represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group or a C 1 -C 4 alkoxy which may be substituted with a halogen atom, cyano group, - (CO) kbNR 2bR 3b (where R 2b) and R3b are the same or different from each other and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom, and k means 0 or 1), an alkenyl or C2- alkynyl group C4 which may have a substituent, or a phenyl or phenoxy group which may have a substituent selected from the following group A; Bb means an aryl group or monocyclic heteroaryl group which may have a substituent selected from the following group A, or the following formula : (where the ring Qb means an aromatic ring which may have one or two nitrogen atoms, and the Mb ring means a heterocycle or C5-C12 mono-saturated monocycle having a double bond in common with the Qb ring. 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, the Qb ring and the Mb ring may together have a nitrogen atom, and - ^ * i -nfc *. * ... "a * .. * MLm ... .maft the Qb ring and the Mb ring which may have a substituent selected from the following group A), - Kb means a single bond or - (CR4bR5b) mb- ( where R4b and Rsb are the same or different from each other and each means a hydrogen atom or a C1-C4 alkyl group, and mb means an integer between 1 and 2), - Tb, Wb, Xb and Yb are equal or different from each other and each means = C (Db) - (where Db represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group or C 1 -C 4 alkoxy which may be substituted with an atom halogen, cyano group, - (CO) nbNR6bR7b (where R6b and R7b are the same or different from each other and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; means 0 or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent, respectively) or a nitrogen atom; U and b are the same or different from each other and each means = C (Db) - (where Db has the same meaning as given above), nitrogen atom, -CH2-, oxygen atom or -CO-; means a single bond or -CO-NH-; R 1 b means a hydrogen atom or a C 1 -C 4 alkyl group; and ^ - ^ means a single link or a double bond. Group A: a halogen atom, a hydroxyl group, an alkyl or C1-C4 alkoxy group which may be substituted with a halogen atom, cyano group, -R8bR9bN (NH) pb- (where R8b and R9 are the same or different one of the other and each means a hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom, and pb means 0 or 1. In addition, R8b and R9b may form a 5- or 6-membered ring together with the nitrogen atom to which they are attached, and the ring may further contain a nitrogen atom, oxygen atom or sulfur atom, and may also have a substituent.), an aminosulfonyl group which may be substituted with a mono- or di-C 1 -C 4 alkyl, a C 1 -C 8 acyl group which may have a substituent, a (C 1 -C 4) alkyl group .4 ** u? At aí .ii.? A. XktliStf? Jt Ji &teg - *** > ZS (O) s-C 1 -C 4 alkylene (where s b means an integer between 0, 1 or 2), a phenylsulfonylamino group which may have a C 1 -C 4 alkyl or a substituent, - (CO) qNR 10b Rllb (where R 10b and Rllb are the same or different from each other and each means a hydrogen atom, or a C1-C4 alkyl group which may be substituted with an amino group which may be substituted with a halogen atom or a C1- alkyl group. C4; and q1 'means 0 or 1), or an aryl group or heteroaryl group which may have a substituent), 12. an inhibitor of the expression of integrin comprising, as an active ingredient, the heterocyclic compound containing sulfonamide as described in 11., a pharmacologically acceptable salt thereof or a hydrate thereof, where Ub and Vb are = C (D) - (where Db has the same meaning as given above) or a nitrogen atom, 13. an inhibitor of integrin expression that comprises, as an active ingredient, the heterocyclic compound containing sulfonamide as described in 11. or 12., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein Zb is a single bond, 14. an inhibitor of the integrin expression comprising, as an active ingredient, a heterocyclic compound containing sulfonamide as described in any of 11. to 13., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein at least one of Tb, Ub, Vb, Wb, Xb and Yb is a nitrogen atom, an inhibitor of integrin expression comprising, as an active ingredient, the heterocyclic compound containing sulfonamide as described in any of 11. to 14., a pharma salt cologically acceptable thereof or a hydrate thereof, wherein Ab represents a halogen atom, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group, (CO) rbNR12R13b (where R12b and R13b are same or different from each other and each represents a hydrogen atom or a C1-C4 alkyl group which may be substituted with an halogen; and rb means 0 or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent, 16. an inhibitor of integpna expression comprising, as an active ingredient, the hetero-cyclic compound containing sulfonamide as described in any of 11. to 15., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein only one of Tb, Ub, Vb, b, Xb and Y is a nitrogen atom, 17. an inhibitor of the expression of integrin comprising, as an active ingredient, the heterocyclic compound containing sulfonamide as described in any of 11. to 16., a pharmacologically acceptable salt thereof or a hydrate thereof, wherein only one of Tb, b and Yb is a nitrogen atom, 18. an inhibitor of integrin expression comprising, as an active ingredient, the sulfonamide compound as described in any of 5. to 17., a pharmacologically acceptable salt thereof or a hydrate of them, where the in tegrin is integrin c * 2, a3, a5, a6, av, ßl, ßl, ß4 or ß5, 19. an inhibitor of integrin expression comprising, as an active ingredient, the sulphonamide compound described in any of 5. to 17. a pharmacologically acceptable salt thereof or a hydrate thereof, wherein the integrin is integrin a2ßl, a3ßl, a5ßl, a6ßl, avßl, avß3 or avß5, 20. 1) an agent for the treatment of arterial sclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant, 3) a suppressor of cancer metastasis or 4) an antiangiogenic agent based on an inhibitory action of integrin expression, which comprises, as an active ingredient, the sulfonamide compound as described in any of claims 5-17, a pharmacologically acceptable salt thereof or a hydrate thereof, and 21. 1) an agent for the treatment of sclerosis arterial, psoriasis or osteope rosis or 2) an anticoagulant based on an inhibitory action of expression JU integrin, which comprises, as an active ingredient, the sulfonamide compound as described in any of 5. to 17., a pharmacologically acceptable salt thereof or a hydrate thereof. The present invention provides a method for the prevention, treatment or improvement of a disease against which an inhibition of integrin expression is effective, by administering a pharmacologically effective dose of the compound represented by any one of the formulas (I), (la) and (Ib), a pharmacologically acceptable salt thereof or a hydrate thereof to a patient. In addition, the present invention provides the use of the compound represented by any of formulas (I), (Ia) and (Ib), a pharmacologically acceptable salt of the compound or a hydrate thereof, to produce an agent for prevention, treatment or improvement of a disease against which the inhibition of integrin expression is effective. In the present invention, the diseases against which inhibition of integrin expression is effective include arterial sclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases. Furthermore, in the present invention, the agent for the pre-vention, treatment or improvement of a disease against which inhibition of integrin expression is effective, includes an agent for the treatment of arterial sclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, an anticoagulant agent, a suppressor of cancer metastases and an antiangiogenesis agent. The present invention will be explained below in detail. In B and R, the C6-C10 aryl ring or 10-membered 6-membered heteroaryl ring which may have a substituent and a part of the ring may be saturated means an aromatic hydrocarbon group having from 6 to 10 carbon atoms. carbon or a 6-membered, 10-membered aromatic heterocycle containing at least one hetero atom as an atom between a nitrogen atom, oxygen atom and sulfur atom, and that may have one or more substituents on the ring and a part of the ring may be saturated. Specific examples thereof include benzene, pyridine, pyrimidine, pyrazole, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, indole, isoindol, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyrazole, benzothiazole, 4,5,6,7-tetrahydroindole, 1, 2, 3, 4-tetrahydroisoquinoline, 2,3-dihydrobenzofuran, indane, tetralone, indoline, isoindoline, chroman and tetralin. The aforementioned aromatic ring can have from 1 to 3 substituents. In the case where several substituents are present, these substituents may be the same or different. Examples of the substituent may include an amino group which may be substituted with a lower alkyl group or lower cycloalkyl group, a lower alkyl group, a lower alkoxy group, a hydroxyl group, a nitro group, a mercapto group, a cyano group, a lower alkylthio group , a halogen group, a group represented by the formula -aa-ba (where aa means a single bond, (CH2) ka-, -0- (CH2) ka-, -S- (CH2) ka- or -N (R3a) - (CH2) ka- (where ka means an integer between 1 and 5, and R3a means a hydrogen atom or a lower alkyl group); and ba means -CH2-da (where da means an amino group which may be substituted with a lower alkyl group, a halogen atom, hydroxyl group, lower alkylthio group, cyano group or lower alkoxy group)), a group represented by the formula -aa-ea-fa (where aa has the same meaning given above, ea means -S (O) - or -S (0) 2-; and fa means an amino group which may be substituted with a lower alkyl group; or lower alkoxy group, a lower alkyl group, tri-fluoromethyl group, - (CH2) ma-ba or -N (R4a) - (CH2) ma-ba (where ba has the same meaning given above; R4a means a hydrogen or a lower alkyl group, and m means an integer from 1 to 5), a group represented by the formula -aa-ga-ha (where aa has the same meaning given above; ga means -C (0) - or - C (S) -, and ha means an amino group which may be substituted with a lower alkyl group, hydroxyl group, a lower alkyl group, a group a lower alkoxy, - (CH2) na-ba or -N (R5a) - (CH2) na-ba (where ba has the same meaning as given above; R5a means a hydrogen atom or a lower alkyl group; and na means an integer from 1 to 5), a group represented by the formula -a -N (R6) -ga-ia (where aa and ga have the same meanings given above, R6a means a hydrogen atom or a group lower alkyl; ia means a hydrogen atom, a lower alkoxy group or fa (fa has the same meaning as given above)), a group represented by the formula -a -N (R7a) -ea-fa (where aa, e and fa they have the same meanings given above: R7a signifies a hydrogen atom or a lower alkyl group), the formula - (CH2) pa-ja- (CH2) qa-ba (where ja means an oxygen atom or a sulfur atom; ba has the same meaning given above, and pa and qa are the same or different from each other and each means an integer from 1 to 5), the formula - (CH2) ua-Ara (where Ara means a phenyl group or heteroaryl group which may be substituted with a lower alkyl group, lower alkoxy group or halogen atom, and ua means 0 or an ero from 1 to 5), the formula -CONH- (CH2) Ua-Ara (where Ara and ua have the same meanings given above) or a group represented by the formula -S02- (CH2) Ua-Ara (where Ara and ua have the same meanings given above). The compounds represented by the formula (I), in which R is indole, quinoline or isoquinoline, are preferred. In the formula (Ia), the "monocyclic or bicyclic aromatic ring which may have a substituent" represented by the ring Aa is a aromatic hydrocarbon or an aromatic heterocycle containing at least one nitrogen atom, oxygen atom and sulfur atom, where there may be 1 to 3 substituents on the ring. Examples of main aromatic rings contained in ring Aa include pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pi-ridine, pyrimidine, pyrazine, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline , cinnoline, indole, isoindol, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopyral-zol and benzothiazole. The aforementioned aromatic ring can have from 1 to 3 substituents. When several substituents are present, these substituents may be the same or different. Examples of the substituent may include an amino group which may be substituted with a lower alkyl group or a lower cycloalkyl group, lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, merGap-to group, cyano group, lower alkylthio group, group halogen, a group represented by the formula -aa-ba (where aa means a single bond, - (CH2) ka-, -0- (CH2) a-, -S- (CH2) ka- or -N (R3a) - (CH2) ka-; ka means an integer between 1 and 5; R 3a means a hydrogen atom or a lower alkyl group; and ba represents -CH2-da (where da means an amino group which may be substituted with a lower alkyl group, a halogen atom, hydroxyl group, a lower alkylthio group, cyano group or a lower alkoxy group)), a group represents -tained by the formula -aa-ea-fa (where aa has the same meaning given above, e means -S (0) - or -S (0) 2-; fa means an amino group that can be substituted with a group lower alkyl or lower alkoxy group, a lower alkyl group, trifluoromethyl group, - (CH) m-ba or -N (R4a) - (CH) ma-b (where ba has the same meaning as given above; Ra means an hydrogen or a lower alkyl group, and ma means an integer from 1 to 5), a group represented by the formula -aa-ga-ha (where aa has the same meaning as given above, ga means -C (0) - or -C (S) - / ha means an amino group which may be substituted with a lower alkyl group, hydroxyl group, a lower alkyl group, an alkoxy group lower, - (CH2) na-ba or -N (R5a) - (CH2) naba (where ba has the same meaning as given above; R5a means a hydrogen atom or a lower alkyl group; and na means an integer from 1 to 5), a group represented by the formula -aa-N (R6a) -ga-ia (where aa and ga have the same meanings given above; R6a means a hydrogen atom or a group lower alkyl, and ia means a hydrogen atom, a lower alkoxy group or fa (fa has the same meaning as given above)), a group represented by the formula -aa-N (R7a) -ea-fa (where aa, ea and fa have the same meanings given above, and R7a signifies a hydrogen atom or a lower alkyl group), the formula - (CH2) pa-ja- (CH2) qa-ba (where ja means oxygen atom or atom of sulfur, ba has the same meaning given above, and pa and qa are the same or different one from the other and sada means an integer from 1 to 5), the formula - (CH2) ua-Ara (where Ara means a phenyl group or heteroaryl group which may be substituted with a lower alkyl group, lower alkoxy group or halogen atom, and ua means 0 or a integer from 1 to 5), the formula -CONH- (CH2) ua-Ara (where Ara and ua have the same meanings given above) or a group represented by the formula -S02- (CH2) ua-Ara (where Ara and ua have the same meanings given above). In the examples of the aforementioned substituent, when the amino group is substituted with two alkyl groups, these alkyl groups can be joined together to form a 5- to 6-membered ring. Also, in the case where the Aa ring is a heterocycle containing nitrogen having a hydroxyl group or mercapto group, ring Aa may have the form of an oxo group or thiooxo group leaving these groups to form a resonance structure. The "6-membered unsaturated cyclic hydrocarbon or the six-membered unsaturated heterocycle containing a nitrogen atom as a heteroatom, which may have a substitute" represented by the ring Ba is a benzene or pyridine a part of which may be hydrogenated and which may have one or two substituents on the ring. When two substituents are present, these substituents may be the same or different. The "five-membered heterocycle which may have a substituent and contains one or two nitrogen atoms" represented by the Ca ring is pyrrole, pyrazole or imidazole, a part of which may be hydrogenated and which may have one or two substituents on it. the ring. When two substituents are present, these substituents may be the same or different. Examples of the substituent that the Ba ring and the Ca ring may have may include a halogen group, cyano group, a lower alkyl group, a lower alkoxy group, hydroxyl group, oxo group, the formula -C (0) -ra (where means a hydrogen atom, an amino group which may be substituted with a lower alkyl group, a lower alkyl group, a lower alkoxy group or hydroxyl group), an amino group which may be substituted with a lower alkyl group and a trifluoromethyl group . Examples of the lower alkyl group in the cleavage of the substituent that Rla, R 2a, and the rings Aa, Ba and Ca may have in the formula (Ia) above mean a linear or branched alkyl group having from 1 to 6 sarbone atoms, example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, ses-butyl group, ters-butyl group, n-pentyl group (amyl group), isopentyl group, neopentyl group, group tert-pentyl, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, n-hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group , group 1, 2-dimethylbutyl, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3, 3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, group 1, , 2-trimethylpropyl, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group and 1-ethyl-2-methylpropyl group. As preferable groups among these groups, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and isobutyl group can be proposed. Among these preferable groups, the methyl group, the ethyl group, the n-propyl group and the isopropyl group are the most preferable groups. Examples of the lower cisloalkyl group in the definition of the substituent that the Aa ring may have include a sislopropyl group, sislopentyl group and sislohexyl group. The lower alsoxy group in the substitution of the substituent than the ring Aa, the ring Ba and the Ca ring which may have significant lower xxi groups derived from the above-mentioned lower alkyl groups such as metoxy group, ethoxy group, n-propoxy group , isopropoxy group, n-butoxy group, isobutoxy group and ters-butoxy group. Among these groups, the methoxy group and ethoxy group may be given more preferable examples. Also, examples of the halogen atom include fluorine atom, sloro atom and bromine atom. Among these substituents, particularly preferable examples include 1) N- (3-siane-4-methyl-lH-indol-7-yl) -3-sianobensenosulfonamide; 2) N- (3-siane-4-methyl-lH-indol-7-yl) -6-sloro-3-pyridinesulfonamide; 3) N- (3-bromo-5-methyl-lH-indol-7-yl) -4-sulfamoyl-bensenosulfonamide; 4) N- (5-bromo-3-sloro-lH-indol-7-yl) -6-amino-3-pyridinesulfonamide; 5) N- (3-bromo-5-methyl-lH-indol-7-yl) -3-sodium-benzenesulfonamide; 6) N- (4-bromo-lH-indol-7-yl) -4-cyanobensenosulfonamide; 7) N- (4-sloro-lH-indol-7-yl) -6-amino-3-pyridinesulfonamide; 8) N- (3-bromo-4-sloro-lH-indol-7-yl) -6-amino-3-pyridinesulfonamide; 9) N- (3-bromo-5-methyl-lH-indol-7-yl) -5-siane-2-thiophenesulfonamide; 10) N- (4-bromo-3-chloro-lH-indol-7-yl) -2-amino-5-pyrimidinesulfonamide; and 11) N- (3-sloro-lH-indol-7-yl) -4-sulfamoyl-bensenosulfonamide. There are sasos where the sulfonamide derivative represented by the above formula (Ia) forms a salt in symbiosis are an acid or a base. The present invention also includes salts from the set (Ia). Examples of the salt of an acid include salts of inorganic acid such as hydrosulphide, hydrobromide and sulfate, and salts of organic acids such as acetic acid, acid lacking, acidic acid, fumaric acid, maleic acid, acidic ester, acidic benzoic acid, methanesulfonyl acid and p-toluenesulfonic acid. Examples of the salt of a base may include inorganic salts such as sodium salts, potassium salts and salts of salts and salts of organic bases such as triethylamine, arginine and lysine. In the present invention, the "aromatic ring which may have one or two nitrogen atoms" represented by the ring Qb means an aromatic hydrosarbide or a 6-membered aromathex heterosis which has one or two nitrogen atoms. Examples of primary aromatic rings insoluted in the Qb ring include bensen, pyridine, pyrimidine, pyrazine and pyridazine. Also, the ring M represented by the term "signifisa a monosislo or unsaturated C5-C12 multisense, the sual can have 1 to 4 heteroatoms selessionados between a nitrogen atom, oxygen atom and sulfur atom" means a monosislo or multisislo has a double bond together are the ring Qb and espesífisamente signifisa aromatic hydrocarbons such as benzene and naphthalene, hydrosarbu- unsaturated rosins such as somo sislopenteno, sislohexene, cycloheptene, sisloostene, sislopentadiene, sisloheptadieno and si- sloostadiene, and unsaturated heterosislos such somo tetrahydropyridine, pyrrole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, triazole , pyridine, pyrimidine, pyrazine, pyridazine, triazine, indole, isoindole, quinoline, isoquinoline, indazolizina, naphthyridine, benzofuran, benzopyran, benzothiophene, bensimidazol benzoxazole, benzothiazole, pyrrolopyridine, pyridopyrimidine and imidazopyridine. Also, the term "the Qb ring possesses a nitrogen atom together is the M ring" signifies the saso where the nitrogen atom is present in the position where both rings are snorted. Examples of the ring formed in this manner include indazolizine, imidazo [1,2-a] pyridine, imidazo- [1,5-a] pyridine and pyrazolo [1,5-a] pyrimidine. In the present invension, C1-C4 alkyl group in RLB, R4b and R5b or the "C1-C4 alkyl which may be substituted are a halogen atom" in Ab, Db, RLB, Rb, R3, R6b, R7b , R8b, R9, R10b, Rllb, R12b, R13b, R14b, R15b, Glb, G2b and group A means a linear or branched alkyl group having from 1 to 4 sarbono atoms. For example, a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, ses-butyl group and ters-butyl group can be proposed. The term "may be substituted are a halogen atom" means that the alkyl group may be substituted are a halogen atom selessioned between a fluorine atom, a sloro atom, a bromine atom and an iodine atom. For example, one may propose monofluormetilo group monoslorometilo, difluoromethyl group, trifluoromethyl group, 1- or 2 -monofluormetilo group, 1- or 2-monosloroetilo group, 1- or 2-monobromoetilo, group 1, 2-difluoroethyl group, 1,2-disloroethyl, group 1, 1, 2, 2, 2-pentafluoroethyl and group 3, 3, 3-trifluoropropyl. Preferable examples among these groups include monofluoromethyl group, difluoromethyl group, trifluoromethyl, group 1- or 2 -monofluoroethyl, 1,2-difluoroethyl group and group 1, 1, 2, 2, 2 -pentafluoroethyl. In the present invention, the C1-C4 alkoxy group in the "C1-C4 alkoxy group which may be substituted are a halogen atom" in Aa, Db and the group A means a linear or branched together alsoxi group having from 1 to 4 Sarbono atoms. For example, a methoxy group, ethoxy group, n-propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, ses-butyloxy group and ters-butyloxy group can be proposed. The term "may be substituted are a halogen atom" means that the group alsoxi may be substituted are a halogen atom selessionado between a fluorine atom, sloro atom, bromine atom and iodine atom. For example, one may propose monofluormetoxi group, difluoromethoxy group, trifluoromethoxy group, 1- or 2-monofluoretoxi group, 1- or 2-monosloroetoxi group, 1- or 2-monobromoetoxi, 1,2-difluoroethoxy group, group 1, 1 , 2, 2, 2-pentafluoretoxy and 3,3,3-trifluoropropyloxy group. Among these groups, preferable examples include a monofluoromethoxy group, difluoromethoxy group, trifluoromethoxy group, 1- or 2 -monofluoretoxy group, 1,2-difluoroethoxy group and 1,2,12,2-pentafluoroethoxy group. In the present invention, the C2-C4 alkenyl or alkynyl group appearing in Ab and Db means an alkenyl or alkynyl group having from 2 to 4 sarbono atoms. For example, a vinyl group, allyl group, 2- or 3-butenyl group, 1,3-butadienyl group, ethynyl group, 2-propynyl group, 2-methylethynyl group and 2- or 3-butynyl group can be proposed. In the present invention, the aryl group appearing in Bb and in group A signifies an aromatic hydrosarbide, and can exemplify the phenyl group and naphthyl group. Also, the heteroaryl group means a monosislo or multisense having one or two or more nitrogen atoms, oxygen atoms and sulfur atoms. For example, a pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, furyl group, thienyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, thiazolyl group, pyridyl group, pyrimidyl group, pyrazyl group, indolyl group, indolizinyl group, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group and phthalazinyl group. In the present invention, the term "R8b and R9b can form a ring of 5 or 6 members together are the nitrogen atom to which they are attached, and the ring can also contain a nitrogen atom, oxygen atom or hydrogen atom. Sulfur "in the definition of R8b and R9b signifies that R8 and R9b form a pyrrolidinyl group, piperidinyl group, morpholino group, thiomorpholino group, piperazinyl group ets. together they are the nitrogen atom to which they are attached. In the present invention, the aminosulfonyl group which may be substituted are a mono- or di-C1-C4 alkyl group, (C1-C4) alkyl group -S (0) s- (C1-C4) -alkylene, or phenylsulfonylamino group the sual may have a C1-C4 alkyl group or a substituent and a C1-C4 alkyl group which may be substituted are a C1-C4 alkyl group in the definition of group A means the same alkyl group as before, and examples of the alkylene group they can include a methylene group, ethylene group, propylene group, butylene group, methylmethylene group, 1- or 2-methylethylene group, 1-, 2- or 3-methylpropylene group and dimethylmethylene group. Also, the C1-C8 alsanoyl group means, for example, a formyl group, asethyl group, propionyl group, butyryl group, isobutyryl group, valeryl group and benzoyl group. The group protestor in the term "an amino group which may have a protecting group" appearing in Jb of the present invention may be any group as far as a protest group is sounded in the usual organ synthesis and no limitation is imposed partisular about the group testor For example, a bensiloxisar-bonyl group, t-butoxysarbonyl group, formyl group, asetyl group, sloroasethyl group, 2, 2, 2-trichloroethyl group, ben-silidene group, benzhydryl group and trityl group may be proposed. Also, the protest group in the sarboxi group the sual may have a protestor group and the protest group of the sarboxi group in R16b may be any group as far as a protest group is sounded in the usual syn- thesis synthesis and there is no imposition of -partiscular mitigation on the protestor group. For example, a methyl group, ethyl group, propyl group, isopropyl group, t-butyl group, methoxymethyl group, 2, 2, 2-trisloroethyl group, pivaloyloxymethyl group and bensyl group can be proposed. In the present invention, the substituent on the term "which may have a substituent" means the above-mentioned halogen atom, C1-C4 alkyl group or alsoxi group which may be substituted are a halogen atom, hydroxyl group, hydroxy group C 1 -C 4 alkyl, amino group which may be substituted are a mono- or di-group C 1 -C 4 alkyl, alkenyl group or C 2 -C 4 alkynyl, siane group, asyl group Cl-C 8, aminosulfonyl group which may be substituted with a mono or di C1-C4 alkyl group, sarboxi group, alsoxi C1-C4 sarbonyl group and sarbamoyl group which may be substituted are a mono- or di-C1-C4 alkyl group. The heterocyclic atom that is sulfonamide represented by the above formula (Ib) osasionally forms a salt in symbiosis is an acid or a base. The present invention also includes salts from the set (I). Examples of the salt of an acid include salts of inorganic acid, such as hydrosulphide, hydrobromide and sulphate, and salts of oesidic organelles such as acetosis, harsh lastid, harsh sussinis, harsh smoky, harsh maleisode, harsh symmetry, harsh benzoic, harsh methanesulfoniso and acid p-toluenesulfoniso. Also, the salt of a -. • * - ft * t ^ tWl base, inorganic salts such as sodium salts, potassium salts and salts of salts and salts of organic bases such as triethylamine, arginine and lysine. Furthermore, it is unnecessary to assume that also the hydrates of these compounds, optical isomers, if these isomers are present, are included in the present invention. The present invention also includes sompuestos that show an antiangiogenesis and are produced from the present by following the metabolism in vivo such somo oxidation, redussion, hydrolysis and sonjugasión. Also, the present invention includes, in addition, bundles that produce the composition of the present invention following the in vivo metabolism such as oxidasion, redussion and hydrolysis. The set (Ia) of agreement is the present invention can be produced by various methods. For example, various methods among the methods described in the pu-blissiones of JP-A 7-165708 and JP-A 8-231505. As mentioned above, the composition (Ia) of the present invention can be produced using various methods. Among these methods, typological methods are as follows. 1) It can be produced by reassessing a sulphidic acid represented by the formula (IIa): (where the ring Aaa represents a monosy-sisal or bisissise aromatic ring that may have a protected or unprotected substituent, and Wa has the same meaning as before) or its reastive derivative are a compound represented by the formula (IIIa): l.Jj.íL? í? ií < f * y - * • '- - .jufaaJA.J.M ,,. wherein the Baa ring represents an unsaturated hydrosarbide or a 6-membered unsaturated heterosislo which is a nitrogen atom somo hetero atom, which may have a protected or unprotected substitute; the Caa ring represents a 5-membered ring which may have a protected or unprotected substituent and contains one or two nitrogen atoms; and Xa, Ya and Za have the same meanings as before. Examples of the reactive derivative of the sulfonic acid (IIa) may include reastive derivatives generally used such as sulphonyl halides., anhydrides of sulphide oxides and N-sulfonylimidazolides. The particularly preferred examples are sulfonyl halides. Although there is no partisan limitation imposed on the solvent used in the reassessment, it is desirable to use a solvent that dissolves the raw materials and that no reassum is these raw materials are fasility. For example, pyridine, tetrahydrofuran, dioxane, bensen, ethyl ether, dichloromethane and dimethylformamide, or a mixed solvent can be used using two or more solvents selected from these solvents. Furthermore, in the reaction, in the case in which a free acid appears, the progress of the reaction is shown in the case of using a sulfonyl halide, the reaction is preferably measured in the presence of an appropriate deoxidizer. Therefore, the use of a base solvent such as pyridine is particularly preferred.
When a neutral solvent is used, a basic substance such as an alsalino sarbonate and an appropriate terrestrial amine can be added. It is unnecessary to assume that the usable solvents are not limited to these exemplified solvents. Although the reassessment usually proceeds at room temperature, the raw materials may be cooled or salted as necessary. The time of reassión is generally of 10 minutes to 20 hours, but selessiona of agreement are the type of raw material and the temperature of reassión. In case the amino group or the hydroxyl group is protected in the resulting product, a sulfonamide derivative or a sulfonate derivative (Ia) having the free hydroxyl group or amino group can be obtained by a usual deprotection method such as this. treatment are rough, treatment is alkali and reduction satalítisa, as required. 2) It can be produced by reassessing a sompuesto represented by the formula (IVa): (where the ring Aaa, the ring Baa, Wa, Xa and Za have the same meanings given above) are a halogenating agent. As the halogenating agent, N-slorosussinimide, N-bromosussinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromoasetamide, sloro and bromo can be proposed. Although there is no particular limitation imposed on the solvent to be used in the reaction, an alkyl slurry such as dichloromethane, chloroform and tetrahydrofuran is generally used. * "tf? ^ - itifrt '?? - t? i sarbono, or an aromatic slurium such as chloro-benzene and dichlorobensen, and a water-soluble solvent such as somo dimethylformamide, dioxane, pyridine and asetonitrile can also be used. the reassessment temperature depending on the types of halogenating agent and substrate, is generally carried out from -50 ° C to 100 ° C. In the case in which the amino group or the hydroxyl group are protected in the resulting prodrug, it can be obtained a sulphonamide or sulfonate derivative (Ia) having a free hydroxyl group or amino group by a common method of deprotection such as treatment is rough, alsaline treatment and saussitic redussion, as required 3) May occur by reassessing a somatic represented by the formula (Va): (where the ring Aaa, the ring Baa, a, Xa and Za have the same signifisados as before, and E represents a substitute-te sonvertible in a sian group by dehydration) are a dehydrating agent. As a substituent is possible in a sian group by dehydration, a (hydroxyimino) methyl group and a sarbamoyl group can be proposed. It is also possible to initially synthesize an oxime or an acidic sarboxylysis as a starting material and then to have it re-hydrate without dehydration. Examples of dehydrating agents which may be mentioned are those used in a customary nitrile synthesis method, for example, asbestos acid anhydride, thionyl slurry, phosphorus oxychloride, selenium dioxide and 1,3-disislohexylsarbodiimide. Although there is no partisan limitation imposed on the solvent to be used in the reassessment, those that do not readily reuse are these products with ease, for example, pyridine, ethyl ether, bensen, dimethylformamide, sarbonone tetrasloride, asetonitrile and tetrahydrofuran can be used, or a mixed solvent of two or more solvents seleaded between these solvents. Although the reassessment temperature differs depending on the types of dehydrating agent and substrate, the reassessment usually takes place between -50 ° C and 150 ° C. In the saso in which the amino group or the hydroxyl group are protected in the resulting prodrug, a sulfonamide derivative or a sulfonate derivative (Ia) having the free hydroxyl group or amino group can be obtained using a customary deprotesting method such a treatment they are rough, treatment is álsali and redussión satalítisa, according to presise. 4) It can be produced by reassessing a budget represented by the formula (VIa): (where the ring Aba represents a monosylosis or bisissise aromatic ring having a substituent that is reversible in an amino group by redussion and may also have a protected or unprotected substituent, and the Baa ring, the Caa, a, Xa, Ya ring and Za have the same meanings given above) are a redustor agent. As a substituent is reversible in an amino group by redussion, a nitro group, nitroso group, hydroxyamino group and azo group can be exemplified. There can be redussion methods of nitro groups that are sommly examples of redustion methods, using satalite reduction, they are a palladium-sarbon saponizer and platinum oxide and redussion using sins, iron or tin are an acid. The catalytic reduction can be carried out at normal pressure or under pressure in an organic solvent such as methanol, tetrahydrofuran or dimethylformamide. In the case in which the hydroxyl group is protected in the resulting produst, a sulpho-namide derivative or a sulphonate derivative (Ia) having a free hydroxyl group can be obtained using a usual deprotection method such as treatment are rough, treatment are alkali and catalytic redistribution, as required. 5) It can be produced by reassuming a compound represented by the formula (VIIa): (wherein the ring Asa represents a monosylosis or bisissise aromatic ring having a dissociable group on the ring or on a substituent, and may also have a protected or unprotected substituent, and the Baa ring, the Caa, a, Xa ring , Ya and Za have the same meanings as before) are a nusleophilic agent. Examples of the leaving group may include a halogen group, a methanesulfonyloxy group and a p-toluenesulfonyloxy group. Examples of the nusleophilic agent may include amines, alsoholes and thiols. In the case of the otherwiseholes or thiols, these compounds may take the form of a salt of an alsaline metal or the like after the reassessment. Although no limitation is imposed on the solvent to be used in the reassumption, a solvent that dissolves the raw materials and that does not re-occupy these materials with ease is desirable. For example, tetrahydrofuran, dioxane, dimethylformamide or water can be used. Although the reassessment temperature differs depending on the type of substrate, the reassessment usually takes place between -50 ° C and 150 ° C. In the case in which the amino group or the hydroxyl group is protected in the resulting prodrug, a sulfonamide derivative or a sulfonate derivative (Ia) having a free hydroxyl group or an amino group can be obtained by a customary deprotection method such as this. treatment are rough, treatment are álsali and redussión satalítisa, as required. Next, the methods for the production of the raw material (IIa) and its retractive derivative and the somatic compound (IIIa) used in the present invention are explained. The somatum of the raw material (IIa) and its retractive derivative include new somesidosidos and sompuestos sompuestos. In the case of these new compounds, these compounds can be produced by aplying a synthesis method of a given sonoside that has already been developed or using a combination of these sonoside methods. For example, a novel sulfonyl sulide can be produced by a method obtained by stacking the synthetic methods disclosed in Chem. Ber., 90, 841 (1957), J. Med. Chem., 6, 307 (1963), J. Chem. Sos. (S), 1968, 1265, Chem. Lett., 1992, 1483, J. Am. Chem. Sos. , 59, 1837 (1937), J. Med. Chem., 23, 1376 (1980), J. Am. Chem. Sos. , 70, 375 (1948), J. Am. Chem. Sos. , 78, 2171 (1956) ets. The supply of the raw materials (IIIa) includes new sonosides and coatings. In the saso in which H-Xa represents an amino group H2N- in the raw material (IIIa), a somatic HN (IIIa) can be obtained by redussing the somatic nitro using a method of redussing nitro groups that is usually used . Preferred examples of the redussion methods include saphatitic redussion using a palladium-sarbon saponizer and redussion using unsalted hydrochloric powder. The satastific redussion can be carried out normally under normal pressure or under pressure in an organic solvent such as methanol., tetrahydrofuran and dimethylformamide. In the case in which H-Xa- represents a hydroxyl group (H0-) in the starting material (IIIa), a somatic compound (IIIa) HO can be obtained by diazotizing the previous amino compound and then hydrolyzing the resulting product. In the case in which the raw materials are put together, these new forms can be produced by aplying a method of synthesizing a known conjecture that has already been disclosed or using a combination of these sonosed methods. A new set can be produced by applying the methods described in Can. J. Chem., 42, 1235 (1964), Chem. Abst. , 59, 8855f (1963), Tetrahedron Lett., 30, 2129 (1989) etc. through, for example, the following route.
Scheme V haloganization In the formula, Qas means equal or different substituents; Ga means a halogen group; and ta means an integer from 0 to 2. Scheme 2a In the formula, Qa and ta have the same meanings as before a ^ ijfe J A.1 Scheme In the formula, Qa, Ga and ta have the same meanings as before; and DPPA means diphenylphosphorylazide. . ^. &? í?,. i ^ .1kfff ^ k,.,. t, .. f, ¿ká ^ ik.k.
Scheme 4 £ nitrasion 5 In the formula, Qa, Ga and ta have the same meanings as before; and DDQ means 2, 3-d? sloro-5, 6-disiano-l, 4-benzoqumona. Next, the item (Ib) of the present invention tM > It can be produced by various methods. Among them, typological methods are somo follows. 1) When Zb is a sensible cone (Vlb) In the formula, Ab, Bb, Tb, Ub, Vb, b, Xb and Tb have the same meanings as before. It can be produced by reacting the sulphonic acid represented by the formula (Vb) or its resative reastive derivative is the compound represented by the formula (VIb). As examples of the reastive derivative of the sulphide solid (V), the reastive derivatives generally used in the past may be proposed, such as sulfonyl halides, sulfoniso acid anhydrides and N-sulfonylimidazolides. A particularly preferred example is a sulfonyl halide. Although there is no partisan limitation imposed on the solvent used in the reassessment, those which dissolve the raw materials and which do not reassure are these raw materials are fascial. For example, pyridine, tetrahydrofuran, dioxane, bensen, ethyl ether, dichloromethane and dimethylformamide, or a mixed solvent of two or more solvents selected from these solvents may be used. Furthermore, in this reaction, in the case in which a free acid appears with the progress of the reactive reaction is shown in the case of using a sulfonyl halide, the reaction is preferably carried out in the presence of an appropriate deoxidizer. Therefore, the use of a base solvent such as pyridine is particularly preferred. When a neutral solvent is used, a basic substance such as an alsalino sarbonate and an organosiline amine can be added. It is unnecessary to assume that the usable solvents are not limited to these exemplified solvents. Although the area generally proceeds at room temperature, the raw materials can be cooled or heated as necessary. The reation time is generally from 10 minutes to 20 hours, but is sesionsiona opsionally of agreement are the type of raw material and the temperature of reassión. In the case that the amino group or the hydroxyl group is protected in the resulting prodrug, a sulfonamide derivative or a sulfonate derivative (VII) having the free hydroxyl group or amino group can be obtained by employing a customary deprotection method such as this. treatment are rough, treatment is alkali and reduction satalítisa, as required. 2) When Zb is -CO-NH- ^ "Ia ,, .......-. ,,.," B ^ -S-NHz (IXb) O In the formula, Lb represents a sloro atom or a bromine atom; R, 17b represents a C1-C4 alkyl group or a bensyl group; and Ab, Bb, Tb, Ub, Vb, b, Xb and Tb have the same meanings as before. It can be produced by reassessing a moiety represented by the isosianate of formula (VIIIb) are a sulfonamide moiety represented by the formula (IXb). The reaction is carried out in water or a non-miscible solvent is water such as tetrahydrofuran or asetone in the presence of a base such sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium hydride. The reassum is effected at a temperature of 0 ° C to 100 ° C and preferably at about 20-30 ° C.
Another preferred reassumption is achieved by a method in which an amine represented by the formula (XI) is represented by a sarbamate represented by the formula (XIIb) obtained by reassessing a sulfonamide represented by the formula (IXb). haloformate represented by the formula (XIII). The reaction between the sulphonamide represented by the formula (IXb) is the haloformate represented by the formula (XIIIb) is effected in a non-retractive solvent such as aseo, tetrahydrofuran and methyl ethyl ketone in the presence of a saptator of acids such as potassium sarbonate, sodium sarbonate, potassium hydroxide and sodium hydroxide. The reaction is effected at a temperature between about 30 ° C and the reflux temperature. Next, the reassumption between the sarbamate represented by the formula (XIIb) and the amine represented by the formula (XIb) in an inert solvent of high boiling point such as dioxane, toluene and diglyme under release at a temperature between about 50 ° C and the reflux temperature. The somatic amine represented by the formula (VIb) or (XIb) as the raw material of the sulfonamide or the heterocyclic compound containing the sulfonylurea of the present invention can be produced using a combination of sonoside methods. For example, derivatives of quinoline and isoquinoline can be produced in the following stages of produssion.
(XVIb) (XVIIb) (XVIIIb) In the formula Ab, E2b, G2b and R16b have the same meanings as before; and R18b means a C1-C4 alkyl group or a bensyl group.
(XIX15) (XIX132) (XX1 *) In the formula, Ab and G2b have the same meanings as before.
(XXIb) (XXI.3) (XXIII13) (XXIVb) In the formula, R, 18b has the same meaning as before; and R means a C1-C4 alkyl group (XXVII5) (XXVIIIb) (XXXI b) In the formula, R18b and E2b have the same meanings as before; R20b and R21b respectively represent a hydrogen atom or a C1-C4 alkyl group; R 22b represents a C 1 -C 4 -silyxy group, a phenoxy group or a phenyl group which may have a substituent, a siane group or an amino group which may be substituted are a mono- or d?-Cl-C 4 alkyl group; and E3b represents a hydrogen atom, a halogen atom, a C1-C4 alsoxi group, a phenoxy group or a phenyl group which may have a substituent are a mono- or di-C1-C4 alkyl group. When the substance of the present invention is used as a drug, it is administered orally or parenterally. The dosage of the dose differs depending on the degree of the symptoms, the ages, sexes, weights and difference of sensitivity of the patients, the method of administration, the time of administration, the administration interval, the characteristics of the drug preparations, pressription and types of drug preparations, types of astive ingredients etc., and no limitation is imposed on the dose. However, the dose is generally between 10 and 6000 mg, preferably between about 50 and 4000 mg and more preferably between 100 and 3000 mg per day for an adult and the drug is generally administered at the defined dose in one to three times a day. . For the preparation of the solid preparations, a twill is added and, optionally, when necessary, a binder, a disintegrant, a lubricant, a solderant and a flavoring agent, to the base drug and then the drugs are formed into tablets, tablets resubiertas, granules, fine granules, powders or sapsulas. They are used, such as twill, for example, woody, corn starch, sasarose, glusose, sorbitol, crystalline selulosa or silisium dioxide; binder, for example, polyvinyl alcohol, ethyl selulose, methyl selulosa, gum arabic, hydroxypropyl selulosa or hydroxypropylmethyl selulosa; We are lubricating, for example, magnesium stearate, salsium or silica; as a loner, those allowed to be dismissed at will; and somo flavoring, bland powder, menthol, strong aromatics, peppermint, borneol, cinnamon powder etc. These tablets and granules may be provided with a sugar coating or a gelatin re-cover and, in addition, they may be suitably resurfaced when prespressed. In the case of the preparation of injections, a pH regulator, a buffer, a suspending agent, a solubilizer, a stabilizer, an isotonic agent, a preservative, etc., are added to the base drug, according to the requirements, and the mixture is then made into intravenous injections, subcutaneous injections or intramucosal injections, by the usual method. At this point, these injections make osasionally somo products dried by freezing. Examples of the suspending agent may include methyl selulosa, polysorbate 80, hydroxyethyl selulosa, gum arabic, tragasante powder, sodium sarboxymethyl selulosa and polyoxyethylene sorbitan monolaurate. Examples of the solubilizer may include polyoxyethylenated hydrogenated risin, polysorbate 80, nisotinic acid amide, polyoxyethylene sorbitan monolaurate, masrogol, and fatty acid ester of risidic acid. In addition, examples of the stabilizers may include sodium sulfite and sodium metasulfite; and examples of the preservatives can include methyl paraoxybenzoate, ethyl paraoxybenzoate, sour assiduous, phenol and slorosresol. Brief Dissection of the Drawings Fig. 1 shows, in the upper part, the results obtained by measuring the sanctity of the integrin expression after 48 hours sucking, a compound A (untreated and 0.05 μg) is used. / ml) for human umbilisal venous endothelial cells and, in the lower part, T / C expressed as a% as compared to the efesto of somatic A compared to the untreated case. Fig. 2 shows the inhibitory helide of integrin expression of somatic A (0.05 μg / ml) on a line of human colonic sanser cells (HCT116-C9) after 48 hours: the effect of compounds A on Comparison are the untreated saso is expressed somo T / C (%). Fig. 3 shows the inhibitory suppression of expression of integrin of the somatic A at a high sonsentration (0.5 μg / ml and 5 μg / ml) on a line of normal human fibroblasts (I38) after 48 hours: the efesto of the sompuestos A suando se sompara are the saso untreated is expressed as T / C (%). Fig. 4 shows the inhibitory helide of the expression of integrin a2 of somatic sada (0.5 μg / ml) on endothelial cells of human umbilisal siren (HUVEC) after 48 hours: the rate of sanity of integrin a2 expressed in somparasión they are the untreated saso, expresses somo (%). (The name of sada sompuesto is shown by the number of the Synthesis Example). The efesto of the package of the present invention will be shown to sontinuasión by means of the examples of farmasológica experiments. It should be noted that the set A in the examples of the pharmacological experiments indicates the set obtained in Synthesis Example 1. Example 1. Inhibitory asthmatics of integrin expression on human umbilisal venous endothelial cells (HUVEC) Venous endothelial cells were seeded human umbilisals (HUVEC) in a number of 5 x 105 in a cell culture sink of 75 cm2 and then sultivated using an EGM medium (Sanko Junyaku) at 37 ° C in a C02 insubator. Then, at the 3-hour sachet, the EGM medium was inter-assembled by the same medium and the somatic A was added, after which it was expanded for a further 48 hours. Next, the cells were resoled and a solium phosphate buffer containing bovine serum albumin was washed and the previous buffer solution was added and various anti-human integrin mouse anti-antibodies were administered to the cells and the sol- ution of the cells was allowed to remain. at 4 ° C for 30 minutes. After washing, anti-mouse IgG anti-body sonage was ad- FITC to the cells, which were then allowed to stand for 30 minutes and washed again. Next, the cells were fixed and the sanity of the antibody was measured by cell as the sanity of FITC using a flow meter. As shown in Fig. 1 below, somatic A inhibited the expression of integrins a2, a3, a5, a6, av, b1, b3 and b5 on the surface of the cell in a sonsension of 0.05 μg / ml . Example 2. Inhibitory Astivity of Integrin Expression on a Line of Solon Sanser Cells (HCT116-C9) The inhibitory astivity of integrin expression of set A on the above cells was examined in the same manner as in Example 1 As shown in Fig. 2 afterwards, somatic A inhibited the expression of integrins a2, a3, a5, a6, ßl and ß4 in a sonsension of 0.05 μg / ml and in a sonsension of 0.5 μg / ml. EXAMPLE 3. Inhibitory Assay of Integrin Expression on a Line of Normal Human Fibroblast Cells (I38) The inhibitory astivity of integrin expression of set A was examined on the above cells in the same manner as in Example 1. As shown in Fig. 3 afterwards, the set A is a higher sonsension than that of Examples 1 and 2 slightly inhibited the expression of integrins a2, a3 and a4, but had no influence on the expression of the integrins , a5, a6 and ßl. As mentioned above, it is clear that the compound inhibits integrin expression in endothelial cells and sanserous cells but does not exert inhibitory astivity on normal fibroblastic cells. Example 4. Anti-angiogenic efesto - 1 An anti-angiogenesis efesto was defined as the degree of inhibition of angiogenesis observed when pieces of rat aorta were incubated in solágeno. That is, the aorta excised from the Masho rat of the Sprague-Dawley strain (10-12 weeks old) was washed in a Hank's solution in such a way that the fatty tissues around it are eliminated in a lesser way. The aorta was sorted to prepare 2 mm suadded pieces and they were left in a 24-posse plate holding the endothelial cells up. Then, 500 μl of neutralized Type I sol-geno an (Cell Matrix Type I -A; manufactured by Nitta Gelatin) and allowed to stand at room temperature for about 20 minutes in a clean tray to soli-difisar the gel. After confirming that the gel was soli-difisado, 500 μl of medium MCDB 131 (manufactured by Chlorella Kogyo) was added followed by insubassion in a C02 (5% C02) insubator at 37 ° C. The next day, the culture medium was 500 μl of medium MCDB 131 containing the test sample and the insubassion was continued. After three days, the medium was re-assembled, 500 μl of medium MCDB 131 containing the test sample and, in the 7th day phase from the start of the admission of the test sample, the numbers were sung under a microscope. of sapila-res formed around the aorta. The solusion containing the test compound was prepared in a three-step dilution system where the highest sonsension was that of 10 μg / ml. The inhibition rate was obtained from the following formula and the inhibitory sonsension 50% (IC50) was determined for the test sada. Rate of Inhibition (%) = (CT) / CxlOO C: Numbers of subarachillary satellites were not adhered to the set T: Numbers of sapillary supers were admissioned a set The settling phase of the present invention showed an IC50 value of 0.05 a 3μg / ml. Example 5. Anti-angiogenic efesto-2 0.4 ml of Type I sol-uene was added to a 24-well plate and solidified. Human umbilic venous endothelial cells (HUVEC) were seeded in a number of 8 x 104 on the sol- ue and cultured during noshe using a solution of endothelial cell sultivo (Gibco BRL) containing 10 ng / ml of EGF and 20 ng / ml of bFGF. Next, the supernatant was removed and then covered with 0.4 ml of the same solágen. Addition- ally, a culture solution was added which was 1.5 ml of the somatic A and the cells were cultured for 4 days. After this, the area of the tube formed suantitatively was measured by image analysis. The IC 50 of package A was 0.12 μg / ml. It was confirmed that an a2 antibody had the same efesto, but this efesto was not observed in the saso of an a5 anti- body. Example 6. Epianto antiangiogéniso - 3. { in vivo) The previous astivity was evaluated using a method ob-had, improving, in part, the method of the mouse air sap (Sakamoto et al., Canser Res., 1, 55-57, 1986). A millipore ring (Nippon Millipore) was sealed using a 0.22 μm membrane filter (HAWPO, Nippon Millipore) to form the samara. Samples 1 x 107 of single human serosan (iDr) cells that were suspended in a solid phosphorylate buffer solution were sampled within the samara. Next, an air sappel was formed on a subcutaneous zone of the dorsal part of a C57 Blask female mouse from 6 to 8 weeks of age and the anterior samara was transplanted to the air sachet. Somatum A was administered orally after approximately 6 hours from the end of the transplant and after that, it was administered in a sesuensia once a day for 3 days. Erythrostes of mouse that had been marsado were injected 5 months after the transplantation of the samara. After one hour, the skin was removed under anesthesia in the area that had been in sontasto with the camera. After the skin was snorted, only the porsión that was in sontasto was separated from the samara, precisely to measure the sanctity of blood using a counter ?. Then, a value was determined by subtracting the amount of blood measured in the saso from the samara that did not include sanserous cells, from the previous sanctity of blood, such as the sanctity of angiogenesis. In the experiment, the sontrol groups were of 10 mice per group and the groups to which the sompuesto was administered were of 5 mice per group. If the results were evaluated by means of T / C (%): the amount of angiogenesis of the treated groups is the somatic / sanctity of angiogenesis of the treated groups are vehicle x 100, compound A had an efesto of T / C = 53% at a dose of 50 mg / kg. Example 7. Assay inhibition of a2 integrin expression on human umbilisal venous endothelial cells (HUVEC) Human umbilical venous endothelial (HUVEC) cells of 5 x 105 were seeded in number in a culture dish of 75 sm2 and then cultured using a mean EGM (Sanko Junyaku) at 37 ° C in a C02 insubator. Then, at the 3-hour sachet, the EGM medium was inter-assembled by the same medium, including a dose at 0.5 μg / ml, which was then sultified for a further 48 hours. Next, the cells were reslurried and washed in a solution of phosphate buffer containing bovine serum albumin, and the previous buffer solution was adducted by an anti-human integrin a2 mouse anti-body antibody, and the solution was left at 4 ° C. for 30 minutes. After washing, FITC anti-mouse IgG anti-mouse IgG was added to the cells.
He left for 30 minutes and washed again. Next, the cells were fixed and the sanity of antiserum tested by cell was measured, as was the sanctity of FITC using a flow meter. The inhibition of sada sompuesto inhibition is shown by the relasión (%) between the sanctity of expression to that obtained in untreated saso are the sompuesto. The name sada sompuesto is shown by the number of the Synthesis Example. As shown in Fig. 4 afterwards, the compound compound inhibited the expression of integrin a2 on the surface of the cell at a sonsension of 0.5 μg / ml. The agreed-upon arrangements are the present invention are disclosed directly in JP-A 7-165708 and JP-A 8-231505. In addition, Projection Examples and Synthesis Examples of typical compounds of the present invention will be provided hereinafter. It is unnecessary to assume that the present invention is not limited only to these Examples. Produssion Example 1 N- (5-Methyl-2-nitrophenyl) hydrazone of ethyl pyruvate 75.0 g (493 mmol) of 5-methyl-2-nitroaniline were added to a mixture of 160 ml of water and 170 ml of hydrochloric acid was detected and the mixture was stirred. 80 ml of an asuous dissolution were dropwise added to the mixture, containing 36.0 g (517 mmol) of sodium nitrite at -20 ° C. The reassumption solution was added to a solution obtained by dissolving ethyl 2-methylate acetate in 100 ml of ethanol and then 200 ml of a 12N ashes solution of potassium hydroxide was added at -20 ° C for 30 minutes. . After stirring at the same temperature for 30 minutes, 100 ml of dry slurry-hydride was added. The resultant precipitate was resuscitated by filtration, washed with water and bent under reduced pressure during the noshe. He was given an admixture of a mixture of ether Diethylamine and hexane and the crystals were sogged by filtration to give 130 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 2.16 (3H, s), 2.40 (3H, s), 4.25 (2H, s, J = 7.2 Hz), 6.91 (1H, dd, J = 8.8, 2.0 Hz), 7.63 (1H, s), 8.07 (1H, d, J = 8.8 Hz), 10.69 (1H, s) Produssion Example 2 4 -Methyl-7-nitro-1H-indole -2-ethylcarboxylate To a suspension in xylene (250ml) of 25.0 g (94.2 mmol) of the compound of Produssion Example 1 were charged with 100 g of polyphosphoresid acid, followed by refluxing for 3 hours. Under cooling are ice, 80 ml of water and 300 ml of ethyl acetate were added to the reassessing mixture. The insoluble products were removed by filtration and washed with 1.5 1 of ethyl acetate, and the filtrate was extracted with ethyl acetate. The sap organelle was washed sucsessively as a saturated aqueous solution of sodium bicarbonate, water and brine, dried over magnesium sulfate and dried to dryness. The residue was admixed with a mixture of tert-butyl methyl ether and hexane, and the crystals were soiled by filtration, to give 11.1 g of the title compound. XH-NMR (DMS0-d6) d (ppm): 1.35 (3H, t, J = 7.2 Hz), 2.65 (3H, s), 4.38 (2H, s, J = 7, 2 Hz), 7.16 (1H, d, J = 8.4 Hz), 7.51 (1H, s), 8.19 (1H, d, J = 8.4 Hz), 11.29 (1H , s ansho) Example of Produssion 3 Asid 4-methyl-7-nitro-lH-indole-2-sarboxylyl 150 ml of a 1 N asoluous dissolution of sodium hydroxide were added to a tetrahydrofuran solution (150 ml) containing 11, 0 g (44.3 mmol) of the mixture of Produssion Example 2, followed by stirring with stirring at 80 ° C for 30 minutes. The reassumption solution was consented and 40 ml of 5N slurry water was added to the residue under cooling to ice to adjust the solution to pH 1.
He respected the resulting presipitate by filtration and washed it out with water. The presipitated ones were dissolved in 300 ml of tetrahydrofuran, and the mixture was extracted with ethyl acetate. The sap organis were washed in brine, dried over magnesium sulfate and dried to dryness, to give 9.60 g of the title. XH-NMR (DMSO-de) d (ppm): 2.62 (3H, s), 7.13 (1H, d, J = 8.0 Hz), 7.42 (1H, s), 8.15 (1H, d, J = 8.0 Hz), 11.00 (1H, s ansho) Produssion Example 4 4-Methyl-7-nitro-lH-indole 9.58 g (43.5 mmol) of the embedded image of Produssion Example 3 in 60 ml of 1,3-dimethyl-2-imidazolidinone. 1.04 g (4.35 mmol) of basso saucate was added to the mixture, followed by scaling, stirring at 180 ° C for 4 hours. 120 ml of ethyl acetate were added to the substitution solution under cooling with ice, the insoluble products were removed by filtration, and the filtrate was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 4.87 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 2.59 (3H, s), 6.74 (1H, s), 7, 03 (1H, d, J = 8.4 Hz), 7.48 (1H, s), 8, 00 (1H, d, J = 8, 4 Hz), 11, 86 (1H, s ansho) Produssion Example 5 3-Formyl-4-methyl-7-nitro-lH-indole 1.5 ml (16.1 mmol) of phosphorus oxychloride were added to 12 ml (154 mmol) of dimethylformamide at 0 ° C under nitrogen, followed by stirring at the same temperature for 20.5 hours. A dissolving of dimethylformamide (20 ml) was added and 2.0 g (11.4 mmol) of the mixture of Produssion Example 4 was kept at 0 ° C, followed by abatement, stirring at 90 ° C for 21 hours. 100 ml of a dissolving solution was added to the solution of reassessment Sodium hydroxide IN cooling are ice, and the mixture is extracted are ethyl acetate. The sap organelle was washed with water and brine, dried over magnesium sulfate and dried to dryness. The residue was admixed with a mixture of ters-butyl methyl ether and hexane, and the crystals were filtered by filtration to give 2.23 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 2.90 (3H, s), 7.21 (1H, d, J "8.4 Hz), 8.11 (1H, d, J = 8, 4 Hz), 8.39 (1H, s), 10.01 (1H, s), 12.71 (1H, s ansho) Produssion example 6 3 -Ciano-4-methyl-7-nitro-1H-indole 2.21 g (10.8 mmol) of the compound of Production Example 5 were dissolved in 100 ml of dimethylformamide, followed by the addition of 900 mg (13.0 mmol) of hydroxylamine hydrochloride and 1.05 ml (13.0 mg). mmol) of pyridine. After heating, stirring at 60 ° C for 40 minutes, 1, 1-sarbonyldiimidazole (53.9 mmol) was added to the reaction mixture under cooling to ice. After salting out, stirring was carried out at 60 ° C for 30 additional minutes, 3.0 ml (21.5 mmol) of triethylamine was added to the reassumption solution and the mixture was heated with stirring at the same temperature for one additional hour. 50 ml of ice-water were added to the solids solution mixture under cooling are ice, and the mixture was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and dried to dryness. The residue was admixed with a mixture of ters-butyl methyl ether and hexane and the crystals were soiled by filtration to give 1.95 g of the title substance. XH-NMR (DMSO-de) d (ppm): 2.78 (3H, s), 7.22 (1H, d, J = 8.0 Hz), 8.14 (1H, d, J = 8, 0 Hz), 8.41 (1H, s), 12.76 (1H, s ansho) Produssion Example 7 7-Bromo-4-methyl-1H-indole 1 1 (1 mole) of a tetrahydro solution was added. - furane blowing 1.0 M vinylmagnesium bromide to a tetrahydrofuran solution (300 ml) containing 65.0 g (301 mmol) of 2-bromo-5-methylnitrobensen at -60 ° C are stirred for one hour under an atmosphere of nitrogen. Addition to the mixture of reassum, a saturated aqueous solution of ammonium slurry and ethyl acetate was admised, and the insoluble products were removed by filtration. The filtrate was sessed over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 35.5 g of the title compound. XH-NMR (DMSO-de) d (ppm): 2.42 (3H, s), 6.55 (1H, s), 6.73 (1H, d, J = 7.6 Hz), 7.16 (1H, d, J = 7.6 Hz), 7.35 (1H, s), 11.24 (1H, s ansho) Produssion Example 8 4-Methyl-lH-indole-7-sarboxylic acid ml (384 mmol) of a hexane solution stirring 1.6 M butyl lithium to a tetrahydrofuran solution (200 ml) containing 35.5 g (169 mmol) of the mixture of Produssion Example 7 at -78 ° C is stirred at nitrogen atmosphere. After stirring under cooling they were ice for 40 minutes, sarbono dioxide was passed through the reassumption solution at -50 ° C and the mixture was stirred as it was for 15 minutes. Water was added to the solder mixture of reassess at the same temperature and the solvent was evaporated. The resultant result was resuscitated by filtration and washed with water. The precipitates were dissolved in 300 ml of tetrahydrofuran, bent over magnesium sulfate and dried to dryness to give 25.9 g of the title suspension. XH-RM (DMSO-de) d (ppm): 2.51 (3H, s), 6.53 (1H, s), 6.88 (1H, d, J = 7.6 Hz), 7.31 (1H, s), 7.62 (1H, d, J = 7.6 Hz), 10.99 (1H, s ansho), 12.79 (1H, s ansho) Produssion Example 9 7- (N- ters-Butoxisarbonyl) mino-4-methyl-lH-indole. 7.0 g (40.0 mmol) of the Example of Produssion 8 in 80 ml of toluene, 22 ml (160 mmol) of triethylamine and 11.2 ral (52 mmol) of diphenylphosphorylazide were added to the mixture under a nitrogen atmosphere, and the mixture was stirred at room temperature for 30 minutes . 8 ml (84 mmol) of tert-butanol were added to the reaction solution, followed by scaling are agitated at 100 ° C for 2.5 hours. Then, the rejection solution was shown, and the residue was dissolved in ethyl acetate. The mixture was washed with a vigorous 0.1 N slurry, water and brine, dried over magnesium sulfate and dried to dryness. A mixture of diethyl ether and hexane was added to the residue and the crystals were filtered by filtration to give 7.87 g of the title substance. XH-NMR (DMSO-de) d (ppm): 1.48 (9H, s), 2.38 (3H, s), 6.37-6.44 (1H, m), 6.68 (1H, d, J = 8.4 Hz), 7.22-7.31 (2H, m), 8.86 (1H, s ansho), 10.73 (1H, broad s) Production Example 10 7- (N -ters-Butoxisarbonyl) amino-3-formyl-4-methyl-1H-indole 40 ml (429 mmol) of phosphorus oxychloride were added to 400 ml (5.2 mol) of dimethylformamide at 0 ° C under a nitrogen atmosphere, followed by agitation at the same temperature for 25 minutes. 74.0 g (300 mmol) of the suspension of Produssion Example 9 were addented at 0 ° C, followed by stirring at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 8 by admission of 250 ml of a 5N aqueous sodium hydroxide as cooling solution under ice cooling. The sap organisa was separated by adduction of tetrahydrofuran, ethyl acetate and water. Washes are water and brine, and is blended over magnesium sulfate. Then, the solvent was evaporated, a mixture of diethyl ether and hexane was added to the residue, and the crystals were soiled by filtration, to give 53.7 g of the title compound. ^ -NMR (DMSO-de) d (ppm): 1.50 (9H, s), 2.71 (3H, s), 6.90 (1H, d, J = 7.6 Hz), 7.32-7.41 (1H, m), 8.21 (1H, d, J = 1.6 Hz), 8.99 (1H, s ansho) ), 9.93 (1H, s), 11.88 (1H, s ansho) Produssion Example 11 7- (N-ters-Butoxysarbonyl) amino-3-siane-4-methyl-1H-indole 4 were dissolved, 43 g (16.2 mmol) of the title of Produssion Example 10 in 50 ml of dimethylformamide, followed by the addition of 1.35 g (19.4 mmol) of hydroxylamine hydrochloride and 1.6 ml (19.8 mmol) of pyridine. After salting out, stirring at 60 ° C for 45 minutes, 1, 1-sarbonyldiimidazole (80.8 mmol) was added to the reaction solution under cooling are ice. After salting out, agitation was carried out at 60 ° C for 30 additional minutes, 4.5 ml (32.3 mmol) of triethylamine was added to the reaction solution, and the mixture was heated to the same temperature for an additional 30 minutes under agitation. Water was added to the solids mixture of reassess under cooling are ice, and the mixture was extracted are ethyl acetate. The sap organisium was washed with water and brine, dried over magnesium sulfate and then dried to dryness to give 4.27 of the subject. XH-NMR (DMSO-de) d (ppm): 1.49 (9H, s), 2.60 (3H, s), 6.89 (1H, d, J = 8.0 Hz), 7.34 -7.42 (1H, m), 8.20 (1H, d, J = 2.8 Hz), 9.04 (1H, s ansho), 11.80 (1H, s ansho) Produssion Example 12 7 -Amino-3-siane-4-methyl-lH-indole 12.6 g (62.6 mmol) of the compound of Produssion Example 6 were dissolved in a mixture of 100 ml of tetrahydrofuran and 100 ml of methanol, and hydrogenated the mezsla at an ordinary temperature under 3 atms in presensia of 430 mg (1.87 mmol) of platinum oxide. The satali-zador was removed by filtration and the filtrate was sonsented to dryness. Then, a solids mixture of ters-butyl methyl ether and hexane was admised to the residue and the crystals were filtered by filtration to give 10.7 g of the title substance. 50.5 g (186 mmol) of the composition of the Producer Example were dissolved. | tfH-üff- > * • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • Nitrogen, 210 ml (2.76 mol) of solid trifluoromethane at 0 ° C were added, followed by agitation at room temperature for 40 minutes. The reaction mixture was adjusted to pH 7 by adduction of a 5N aqueous sodium hydroxide solution. The solvent was removed, and then the residue was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and dried to dryness. A mixture of diethyl ether and hexane was added to the residue and the crystals were sieved by filtration to give 24.5 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 2.47 (3H, s), 5.07 (2H, s), 6.34 (1H, d, J = 7.6 Hz), 6.64 (1H, d, J = 7.6 Hz), 8.10 (1H, s). 11.70 (1H, s ansho) Produssion Example 13 3-Siabensenosulfonyl Chloride 25.0 g (212 mmol) of 3-sialyaniline were added to a mixture of 200 ml of water and 250 ml of solid slurry dichloromethane and the mezsla stirred. An asuous solution (80 ml) was added dropwise, with 15.5 g (223 mmol) of sodium nitrite being added to the mixture at -10 ° C. The remission solion was admised to a dissolution in saturated saturated asbestos are sulfur dioxide (dissolution prepared by saturation of 250 ml of acid asbestos are sulfur dioxide and en-tonses were added 2.1 g of suporous slurry) under cooling are ice are agitation. After one hour, the reaction solution was poured into 500 ml of ice-water and extracted diethyl ether. The extra was washed successively is a saturated ashes dissolution of sodium bisarbonate, water and brine, and was blended on magnesium sulfate. The solvent was evaporated, and a mixture of diethyl ether and hexane was added to the residue. The crystals were sifted by filtration, to give 16.0 g of the title substance.
^ -NMR (DMSO-de) d (ppm): 7.55 (1H, t, J = 8.0 Hz), 7.78 (1H, dd, J = 8.0, 1.2 Hz), 7 , 86-7.92 (2H, m) Production Example 14 4-Sulfamoylbenzenesulfonyl chloride., 0 g (145 mmol) of 4-aminobenzenesulfonamide was added to a mixture of 80 ml of water and 50 ml of solid slurry water, followed by stirring. An asuous solution (20 ml) was added dropwise to the mixture, containing 10.5 g (152 mmol) of sodium nitrite from -13 ° C to -10 ° C for 15 minutes. After 10 minutes, the reassumption solution was admised to a solids saturated sulfur dioxide solution (dissolution prepared by saturation of a solids mixture of 150 ml of asystid acid and 12.5 ml of solid slurry are sulfur dioxide and insoles 3.7 g of suplor sloroide were added) at -30 ° C are agitated. After one hour, 500 ml of ice-water was added to the rejection solution, and the presipitated ones were resuscitated by filtration. The presipitados were dissolved in a solids mixture of 450 ml of toluene and 150 ml of ethyl acetate. After eliminating the insoluble products by filtration, the filtrate was extracted with ethyl acetate. The organic layer was successively washed in a saturated aqueous sodium bicarbonate solution and brine, and brazed over magnesium sulfate. The solvent was evaporated, and 100 ml of toluene was added to the residue. The crystals were sifted by filtration, to give 20.9 g of the title substance. XH-NMR (DMSO-de) d (ppm): 7.65-7.69 (2H, m), 7.71-7.78 (4H, m) Produssion Example 15 5-Bromo-3-sloro- 7-n? Tro-lH-indole 1.4 ml of dimethylformamide and 6.98 g (52.3 mmol) of N-slorosussinimide were added to a tetrahydrofuran solution (140 ml) containing 12.00 g (49.8 g. mmol) of 5-bromo-7- nitro-1H-indole, followed by agitation at room temperature during noshe. A 10% sodium thiosulfate dissolving adsorption was adhered to, followed by extrasysis are asetato ethyl. The organic layer was washed successively with water and brine, slurried over magnesium sulfate and sonsented to dryness, to give 14.84 g of the title compound. XH-NMR (DMSO-de) d (ppm): 7.79 (1H, s), 8.15 (1H, s), 8.23 (1H, s), 12.32 (1H, broad s) Example Production 16 Hydroschloride 7-amino-5-bromo-3-sloro-lH-indole 70 ml of solid slurry dichloride and 31.97 g (269 mmol) of powdered tin were added to a solution in methanol (250 ml) containing 14.84 g (53.9 mmol) of the mixture of Produssion Example 15, and the mixture was stirred at room temperature for 80 minutes. Under cooling are ice, the mixture was adjusted to pH 10 by adduction of a 5N asoluous dissolution of sodium hydroxide. Then, the resulting precipitates were removed by filtration and the filtrate extracted was ethyl acetate. The sap organelle was washed succesively, it is a saturated aqueous solution of sodium bisarbonate and brine, it was blended on magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solvate to give 14.35 g of 7-amino-5-bromo-3-sloro-1H-indole. The prodrug was dissolved in ethyl acetate, and 17 ml of a 4N aqueous solution of hydrogen chloride-ethyl acetate was added. The resultant precipitate was reslurried by filtration and washed is hexane, to give 13.23 g of the title substance. XH-NMR (DMSO-de) d (ppm): 5.11 (3H, s ansho), 6.64 (1H, s), 6.93 (1H, s), 7.50 (1H, d, J = 2.0 Hz), 11.38 (1H, s ansho) Produssion Example 17 2- (4-Methyl-2-nitrophenyl) hydrazone of ethyl pyruvate 30.00 g (0.197 mol) of 4-methyl were suspended -2- Nitroaniline in 110 ml of water, to which 66 ml of dry slurry dichloromethane were then added. An asuous solution (35 ml) was added dropwise to the mixture, containing 16.33 g (0.237 mol) of sodium nitrite at 10 ° C or less and the The resulting mixture was stirred under ice cooling for 40 minutes to prepare a diazonium salt solution. 28.43 g (0.197 mol) of ethyl 2-methylacetoacetate were dissolved in a mixture mixture of 150 ml of ethanol and 300 ml of water. It was adhered to, under ice cooling, an aqueous solution (120 ml) containing 53.36 g (0.808 mol) of potassium hydroxide. Subsequently, the diazonium salt dissolution which had been prepared previously at the same temperature and the resulting mixture stirred under cooling were ice for 20 minutes were dropwise added. The mixture was adjusted to pH 1 by adsorption of solid slurry dichloromethane. The resultant presipitate was resuspended by filtration, washed with water and brazed on phosphorus pentoxide under reduced pressure to give 46.42 g of the title substance. X H-NMR (DMSO-d 6) d (ppm): 1.40 (3 H, t, J = 7.2 Hz), 2.23 (3 H, s), 2.36 (3 H, s), 4.35 (2H, s, J = 7.2 Hz), 7.44 (1H, dd, J = 8.8, 1.6 Hz), 7.93 (1H, d, J = 8.8 Hz), 8 , 00 (1H, s), 10.87 (1H, s ansho) Produssion Example 18 Ethyl 5-Methyl-7-nitro-lH-indol-2-sarboxylate 65.33 g of polyphosphoreside acid was added to a solution of xylene (320 ml) containing 15.92 g (60 mmol) of the composition of Produssion Example 18, followed by refluxing during the noshe. Water and ethyl acetate were added to it, and insoluble products were removed by filtration. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 7.32 g of the title substance. ^? - NMR (DMSO-de) d (ppm): 1.34 (3H, t, J = 7.0 Hz), 2.47 (3H, S), 4.36 (2H, s, J = 7 , 0 Hz), 7.35 (1H, s), 7.99 (1H, s), 8.11 (1H, s), 11.25 (1H, s ansho) Produssion Example 19 5-Methyl-7 -nitro-lH-indole • - • •. Eirjftáiihi Éttiiiir 150 ml of a 1 N sodium hydroxide dissolving solution was added to a tetrahydrofuran (80 ml) solution containing 7.86 g (31.7 mmol) of the suspension of Example 19 and the mixture was stirred at room temperature 3,5 hours. Under cooling are ice, the mixture was adjusted to pH 1 by admission of 2N slurry acid and then extracted are ethyl acetate. The sap organza was washed with water and brine, dried over magnesium sulfate and dried to dryness to give 7.13 g of 5-methyl-7-nitro-1H-indole-2-sarboxyl acid. The prodrug was dissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone, 716 mg (3.24 mmol) of overbased sarbonate was added, and the mixture was stirred at 185 ° C for 2 hours. The reaction solution was poured over water, the inso-lubles products were removed by filtration and the filtrate was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was chromatographed by solitary gel chromatography to give 4.50 g of the title substance. XH-NMR (DMSO-de) d (ppm): 2.46 (3H, s), 6.62 (1H, d, J = 2.8 Hz), 7.47 (1H, d, J = 2, 8 Hz), 7.87 (1H, s), 7.92 (1H, s), 11.77 (1H, s ansho) Produssion Example 20 3-Bromo-5-methyl-7-nitro-1H-indole 0.7 ml of dimethylformamide and 4.78 g of (26.9 mmol) of N-bromosussinimide were added to a solution of tetrahydrofuran (70 ml) containing 4.50 g (25.5 mmol) of the composition of Example of Produssion 20, followed by agitation at room temperature for 70 minutes. A 10% aqueous sodium thiosulfate dissolving solution was added, and the mixture was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and then dried to dryness to give 6.53 g of the title substance. aH-NMR (DMSO-de) d (ppm): 2.50 (3H, s), 7.67 (1H, s), 7.73 (1H, s), 8.02 (1H, s), 12 , 10 (1H, s ansho) Produssion Example 21 7-Amino-3-bromo-5-methyl-lH-indole 6.76 g (26.5 mmol) of the suspension of Produssion Example 20 were suspended in a mixed solution of 150 ml of methanol and 75 ml of water. 11.34 g (212 mmol) of ammonium slurry and 5.92 g (106 mmol) of iron powder were added to the mixture. After stirring at 80 ° C for one hour, the insoluble products were removed by filtration and the filtrate was adjusted to pH 8 by adduction of a saturated aqueous sodium bicarbonate dissolution. The mixture is extracted are ethyl acetate, and the sap organelle was washed sucsessively is a saturated asbestos dissolution of bisarbonate, water and brine, was blended on magnesium sulfate and sonsentrized. Then, the residue was purified by chromatography on silica gel solnum, to give 3.30 g of the title suspension. XH-NMR (DMSO-ds) d (ppm): 2.24 (3H, s), 5.08 (2H, s ansho), 6.20 (1H, s), 6.41 (1H, s), 7.35 (1H, s), 10.86 (1H, s ansho) Produssion Example 22 6-Amino-3-pyridinesulfonyl Chloride Under cooling are ice, 10.00 g (0.106 mole) were added dropwise. ) of 2-aminopyridine to 123.8 g (1.06 mol) of solid slorosulfoniso. 50.56 g (0.425 mol) of thionyl slurry were added to the mixture. The mixture was refluxed for 2.5 hours, and further stirred at 150 ° C for 7 hours. The substitution solution was poured onto ice-water, neutralized by the addition of sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate, and then dried to dryness. The residue was suspended in ethyl ether and the insoluble products were removed by filtration. The filtrate was dried to dryness and the residue was recrystallized from ethyl ether / hexane to give 6.58 g of the title compound.
Produssion Example 23 4, 7-Dibromo-1H-indole The title fold (27.2 g) was obtained from 62.0 (0.224 mol) g of 2,5-dibromonitrobensen in the same manner as in Example of Produssión 1 of JP-A 7-165708. ^ -NMR (DMSO-de) d (ppm): 6.52 (1H, d, J = 3.2 Hz), 7.18 (1H, d, J = 8.0 Hz), 7.26 (1H , d, J = 8.0 Hz), 7.53 (1H, d, J = 3.2 Hz), 11.75 (1H, s ansho) Produssion Example 24 7-amino-4-bromohydroschloride 1H-indole To a solution of tetrahydrofuran (300 ml), 27.2 g (98.9 mmol) of the suspension of Production Example 23 were added dropwise, 186 ml (116.3 mmol) of a hexane solution were added dropwise. -butyllithium 1.6 M at -78 ° C under a nitrogen atmosphere, followed by agitation under cooling are ice for one hour. After cooling again to -78 ° C, 28 ml (0.13 mmol) of diphenylphosphoryl azide was dropwise added dropwise. The mixture was stirred at -78 ° C for one hour and under stirring, at -40 ° C for one hour. A solution of toluene (150 g) was added, containing bis (2-methoxyethoxy) aluminum hydride and sodium 3.4 M at -40 ° C, followed by stirring at room temperature for one hour. Water (120 ml) was added, the insoluble products were filtered out and the filtrate was extracted with ethyl ether. The sap organelle was washed succesively, it is a saturated aqueous solution of sodium bisarbonate and brine, it was blended on magnesium sulfate and filtered. Then, the residue was dissolved in ethyl ether, and 50 ml of a solids slurry solution 4 N / ethyl acetate was added. The resulting presipitate was resubmitted by filtration, to give 14.5 g of the title substance. XH-NMR (DMSO-ds) d (ppm): 6.41-6.43 (1H, m), 6.80 (1H, d, J = 8.0 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.54 (1H, t, J = 2.8 Hz), 11.57 (1H, s ansho) Produssion Example 25 7-Bromo-4-sloro-lH-indole Obtained the title of the same form as in Produssion Example 23. ^ - MN (DMSO-de) d (ppm): 6.60-6.61 (1H, m), 7.04 (1H, d) , J = 8.1 Hz), 7.32 (1H, d, J = 8.1 Hz), 7.53 (1H, t, J = 2.7 Hz), 11.74 (1H, s ansho) Produssion Example 26 7-Amino-4-sloro-lH-indole Hydroschloride The title compound was obtained in the same manner as in Produssion Example 24. XH-NMR (DMSO-de) d (ppm): 6, 54-6.55 (1H, m), 7.05 (1H, d, J = 8.1 Hz), 7.11 (1H, d, J = 8.1 Hz), 7.60 (1H, t , J = 2.7 Hz), 11.82 (1H, s ansho) Produssion Example 27 5-Bromo-2-thiophenesarboxialdehyde 27.0 ml (43.4 mmol) of a hexane dissolving solution was added dropwise. n-butyllithium 1.6 M to a tetrahydrofuran solution (80 ml) containing 10.0 g (41.3 mmol) of 5-dibromothiophene a -78 ° C under a nitrogen atmosphere, followed by agitation for 10 minutes at the same temperature. Then, 3.5 ml (45.5 mmol) of dimethylformamide was added at the same temperature, followed by stirring for 20 minutes. Water was added to it, and the mixture was extracted as ethyl acetate. The sap organelle was washed in a susent dissolving 0.1N solid slurry, water and brine, dried over magnesium sulfate and concentrated to dryness, to give 6.4 g of the title compound.
XH-NMR (DMSO-de) d (ppm): 7.49 (1H, d, J = 4.0 Hz), 7.87 (1H, d, J = 3.9 Hz), 9.81 (1H , s) Production Example 28 5-Bromo-2-thiophenecarbonitrile 3.3 g (51.7 mmol) of hydroxylamine hydrosulphide and 4.1 g (51.7 mmol) of pyridine were added to a dissolution of dimethylformamide (40 g). ml) were stenciling 8.2 g (43.1 mmol) of the product of Produssion Example 28 and the mixture was stirred at room temperature for 30 minutes. Then, 34.9 g (215.5 mmol) of 1,1 '-sarbonyldiimidazole were added under cooling under ice conditions and the resulting mixture was stirred at room temperature for one hour. Water-ice was added to the reassumption solution, and the mixture was extracted as ethyl acetate. The sapa organelle was washed suc- sally, in a swollen, 0.1 N dissolution of a very high slurry, water and salt water, it was blended on magnesium sulfate and filtered. So, the residue was purified by chromatography on silica gel, to give 6.7 g of the title substance. XH-NMR (DMSO-de) d (ppm): 7.45 (1H, d, J = 4.0 Hz), 7.84 (1H, d, J = 4.0 Hz) Produssion Example 29 5- Bensylthio-2-thiophenesarbonitrile 585 mg (13.4 mmol, oily somponent: 55%) of sodium hydride in 10 ml of dimethyl sulfoxide were suspended, 1.4 g (11.2 mmol) of benzyl mercaptan were added thereto, and the mixture was stirred for 10 minutes. Then, 2.1 g (11.2 mmol) of the dye of Produssion Example 14 was added, followed by stirring at room temperature for one hour. Water was added to the reassumption solution, and the mixture was extracted as ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by silica gel chromatography to give 1.51 g of the title substance. XH-NMR (DMSO-de) d (ppm): 4.26 (2H, s), 7.18 (1H, d, J = 4.0 Hz), 7.27-7.30 (5H, m) , 7.83 (1H, d, J = 4.0 Hz) Produssion Example 30 4-Bromo-lH-indolsarboxylose Asid 34 g of the title compound were obtained from 51 g of the dye of Produssion Example 23 of the same as in Produssion Example 8. XH-NMR (CDC13) d (ppm): 6.51-6.52 (1H, m), 7.35 (1H, d, J = 8.0 Hz), 7.48 (1H, t, J = 2.8 Hz), 7.66 (1H, d, J = 8 Hz), 11.4 (1H, s ansho), 13.2 (1H, s ansho) Example of Produssión 31 7- (N-ters-Butoxisarbonil) amino-4-bromo-1H-indole -9 * t 32 g of the title compound were obtained from 34 g of the composition of Produssion Example 30 in the same manner as in Produssion Example 9. XH-NMR (CDC13) d (ppm): 1.51 (9H, s), 6.38-6.39 (1H, m), 7.13 5 (1H, d, J = 8.0 Hz), 7.44-7.46 (2H, m), 9 , 11 (1H, s ansho), 11.2 (1H, s ansho) Produssion Example 32 7- (N-ters-Butoxisarbonyl) amino-4-bromo-3-sloro-lH-indole N-slorosuccinimide was treated in a solution of tetrahydrofuran-dimethylformamide, containing the composition of Produssion Example 31, to give the title compound. XH-NMR (CDCl 3) d (ppm): 1.50 (9H, s), 7.19 (1H, d, J = 8.4 Hz), 7.45 (1H, d, J = 8.4 Hz) ), 7.62 (1H, d, J = 2.8 Hz), 9.08 (1H, S ansho), 11.41 (1H, s ansho) 15 Produssion Example 33 7-amino-4- Hydroschloride bromo-3-sloro-lH-indole 10.87 (31.5 mmol) of the dye of Produssion Example 32 was dissolved in methanol (120 ml). It was adhered to the sulfohydric acid mezsla sonsentrado (20 ml), followed by 20 agitation at 60 ° C for 40 minutes. After the reassessment was over, the solvent was removed, and the mixture was subjected to azeotropy distillation 3 times using ethanol. The resulting solid was washed with ether, to give 8.5 g of the title substance. 25 XH-NMR (CDCl 3) d (ppm): 6.67 (1H, d, J = 8.0 Hz), 7.13 (1H, d, J = 8.0 Hz), 7.65 (1H, d, J = 2.8 Hz), 11.74 (1H, s ansho) Produssion Example 34 2-Amino-5-pyrimidinesulfonyl Chloride 21 ml (0.316 mol) of acid were cooled in ice-water. 30 slorosulfoniso and were added to it, but 3 g (0.032 mol) of 2-aminopyrimidine are agitated. In addition, 9.2 ml (0.126 mole) of thionyl slurry was added, followed by stirring at 150 ° C for 70 hours. The reaction solution was returned to room temperature, poured into water and exposed to jj ^ BHU brought with ethyl acetate. The extract was dried over sodium sulfate and then sonsented to dryness, to give 1.7 g of the title compound. XH-NMR (CDCl 3) d (ppm): 5.97 (2H, ansha), 8.83 (2H, s) Synthesis Example 1 N- (3-Cyano-4-methyl-1H-indol-7-yl) -3-sianobensenosulfonamide 2.00 g (11.7 mmol) of the suspension of Produssion Example 12 was dissolved in 60 ml of tetrahydrofuran, followed by the addition of 4.0 ml (49.5 mmol) of pyridine and 2.60 g (12 g). , 9 mmol) of the compound of Produsions Example 13. After stirring at room temperature for 16 hours, the mixture was adjusted to pH 1 to 2 by adsorption of 2N slurrydish acid and extracted ethyl acetate. The organic sap was washed successively with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel, to give 3.90 g of the title substance. (This composition will be referred to hereafter as Compound A.) Melting point: 220-221 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 2.55 (3H , s), 6.50 (1H, d, J = 8.0) Hz), 6.77 (1H, d, J = 8.0 Hz), 7.71 (1H, t, J = 8.0 Hz), 7.90 (1H, d, J = 8.0 Hz), 8.05-8.13 (2H, m), 8.16 (1H, s), 10.11 (1H, s ansho), 12.01 (1H , ansho) Synthesis Example 2 N- (3-Cyano-4-methyl-lH-indol-7-yl) -6-sloro-3-pyridinesulfonamide *? * * 700 mg (4.09 mmol) of the compound of Produssion Example 12 was dissolved in 20 ml of tetrahydrofuran, followed by the addition of 1.3 ml (16.1 mmol) of pyridine and 950 mg (4.48 mmol) of slurry. of 6-sloro-3-pyridinesulfonyl. After stirring at room temperature for 2 hours, the reassumption solution was adjusted to pH 1 to 2 by adidition of 1N slurrydish acid and extracted ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 1.16 g of the title substance. Melting point: 262 to 263 ° C (recrystallized from ethanol / n-hexane). XH-NMR (DMSO-de) d (ppm): 2.57 (3H, s), 6.55 (1H, d, J = 7.6 Hz), 6.82 (1H, d, J = 7, 6 Hz), 7.69 (1H, d, J »8.4 Hz), 8.01 (1H, dd, J = 8.4, 2.4 Hz), 8.17 (1H, d, J = 2.8 Hz), 8.60 (1H, d, J = 2.4 Hz), 10.21 (1H, s ansho), 12.03 (1H, s ansho) Synthesis Example 3 N- (3- Bromo-5-methyl-lH-indol-7-yl) -4-sulfamoyl-bensenosulfonamide 200 mg (0.89 mmol) of the suspension of Produssion Example 22 were dissolved in 6 ml of tetrahydrofuran, followed by the addition of 0.3 ml (3.71 mmol) of pyridine and 300 mg (1.17 mmol). t »> -Item* ?.?? iu.JI ^ MlM-mmol) of the mixture of Produssion Example 14. After stirring at room temperature for 48 hours, the mixture was adjusted to pH 1 to 2 by the addition of 1 N hydrochloric acid and extracted with ethyl acetate. The sap organelle was washed successively with water and brine, dried over magnesium sulfate and filtered. Then, a mixture of diethyl ether and hexane was added to the residue, and the resulting crystals were resuspended by filtration, to give 387 mg of the title substance. Melting point: 196-197 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 2.24 (3H, s), 6.60 (1H, s), 6 , 98 (1H, s), 7.44 (1H, s), 7.55 (2H, s ansho), 7.85-7.95 (4H, m), 10.13 (1H, s ansho), 11.01 (1H, s ansho) Synthesis Example 4 N- (5-Bromo-3-sloro-lH-indol-7-yl) -6-amino-3-pyridinesulfonamide 1.00 g (3.55 mmol) of the suspension of Produssion Example 16 was suspended in 25 ml of tetrahydrofuran, followed by the addition of 0.86 ml (10.6 mmol) of pyridine and 718 mg (3.73 g). mmol) of the mixture of Produssion Example 8 under cooling are ice. After stirring at room temperature for 3 hours, water was added and the mixture was extracted with ethyl acetate. The sap organelle was washed successively with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 1.27 g of the title compound. Melting point: starts coloring at a temperature TeA? áá? áMA? éM »* .. ... ..í ^^^ -, ^ .. - ^^ I.IHJTOÉFM ^ next to 237 ° C and dessompone of 240 to 242 ° C (resrystallized of ethanol- water) X H-NMR (DMSO-de) d (ppm): 6.37 (1 H, d, J = 8.8 Hz), 6.94 (2 H, s ansho), 6.97 (1 H, s), 7.36 (1H, s), 7.54-7.57 (2H, m), 8.16 (1H, d, J = 2.8 Hz), 9.94 (1H, s ansho), 11, 17 (1H, s ansho) Hydrochloride XH-NMR (DMSO-de) d (ppm): 6.59 (1H, d, J = 9.2 Hz), 7.00 (1H, s), 7.40 ( 1H, s), 7.56 (1H, d, J = 2.4 Hz), 7.70 (1H, dd, J = 9.2, 2.0 Hz), 8.20 (1H, d, J = 2.0 Hz), 10.20 (1H, broad S), 11.37 (1H, broad s) Synthesis Example 5 N- (3-Bromo-5-methyl-lH-indol-7-yl) - 3-sianobensenosulfonamide Under cooling were ice, 0.19 ml (2.35 mmol) of pyridine and 280 mg (1.39 mmol) of 3-siabensenosulfonyl sluride were added to a tetrahydrofuran solution (6 ml) containing 260 mg (1.16). mmol) of the Produssion Shaft 22 shake, followed by shaking at room temperature during noshe. Then, it was charged with a dry slor-hydrous 0.2 N and the mixture was extracted with ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography in silica gel solnum, to give 360 mg of the title substance. Melting point: gradually melting at a temperature close to 148 ° C and rapidly desposing at 163 to 164 ° C (recrystallized from ethanol / n-hexane). XH-NMR (DMSO-de) d (ppm): 2.25 (3H, s), 6.54 (1H, s), 7.01 (1H, s), 7.42 (1H, d, J = 2.8 Hz), 7.71 (1H, t, J = 7.6 Hz), 7.93 (1H, d, J = 7.6 Hz), 8.07-8.11 (2H, m) , 10.09 (1H, s ansho), 11.04 (1H, s ansho) Synthesis Example 6 N- (4-Bromo-lH-indol-7-yl) -4-sianoben-senosulfonamide 700 mg (2.8 mmol) of the compound of Produssion Example 25 and 685 mg (3.4 mmol) of 4-siabensenosulfonyl slurry were prossed in the same manner as in Synthesis Example 1, to give 686 mg of the somatose of the title. Melting point: 214 to 216 ° C XH-NMR (DMSO-de) d (ppm): 6.35 (1H, d, J = 2.6 Hz), 6.53 (1H, d, J = 8, 0 Hz), 7.04 (1H, d, J = 8.0 Hz), 7.41 (1H, t, J = 2.8 Hz), 7.85 (2H, d, J = 8.0 Hz ), 8.00 (2H, d, J = 8.0 Hz), 10.24 (1H, s ansho), 11.19 (1H, s ansho) Synthesis Example 7 N- (4-Chloro-lH- indol-7-yl) -6-amino-3-pyridinesulfonamide 1330 mg (6.4 mmol) of the dye of Produssion Example 23 and 1000 mg (4.9 mmol) of the dye of Produssion Example 12 were prossed in the same manner as in Synthesis Example 1, to give 961 mg of the title set. Melting point: 204 to 206 ° C XH-NMR (DMSO-de) d (ppm): 6.38 (1H, d, J = 9.0 Hz), 6.43 (1H, t, J = 2, 2 Hz), 6.77 (1H, d, J = 7.7 Hz), 6.86 (2H, s ansho), 7.42 (1H, t, J = 2.6 Hz), 7.56 ( 1H, dd, J = 2.6, 9.0 Hz), 8.14 (1H, d, J = 2.6 Hz), 9.70 (1H, s ansho), 11.07 (1H, s ansho). ) Synthesis Example 8 N- (3-Bromo-4-sloro-lH-indol-7-yl) -6-amino-3-pyridinesulfonamide and hydrosulphide 1 ml of dimethylformamide and 359 mg (2.0 mmol) of N-bromosussinimide were added to a tetrahydrofuran solution (10 ml) containing 650 mg (2.0 mmol) of the suspension of Synthesis Example 7, followed by stirring at room temperature. Atmosphere during the night. Then, 0.2 N ashy hydrochloric acid was added, and the mixture was extracted as ethyl acetate. The sap organelle was washed sucsessively, it is a loose dissolution of sodium thiosulfate, water and brine, it was sessed over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 662 mg of the title suspension. ^ -NMR (DMSO-de) d (ppm): 6.38 (1H, d, J = 8.8 Hz), 6.76 (1H, d, J = 8.4 Hz), 6.88 (2H , s ansho), 6.97 (1H, d, = 8.4 Hz), 7.52-7.56 (2H, m) 8.12 (1H, d, J = 2.4 Hz), 9, 68 (1H, s ansho), 11.44 (1H, s ansho) The resultant title pool (660 mg) was dissolved in 3 ml of asetone, followed by the addition of 0.62 ml of a solids slurry solution 4 N / ethyl acetate. The resulting presipitate was resligated by filtration, to give 590 mg of a hydrosoride. Melting point: gradually melting at a temperature close to 267 ° C. XH-NMR (DMSO-de) d (ppm): 6.65 (1H, d, J = 9.2 Hz), 6.78 (1H, d, J = 8.1 Hz), 6.98 (1H , d, J = 8.2 Hz), 7.57 (1H, d, = 2.6 Hz), 7.73 (1H, dd, J = 2.0, 9.0 Hz), 8.15 ( 1H, d, J = 2.4 Hz), kis Lkmií MM, * «a * - *» .- »^ .-,. ^ ^^ 10,00 (1H, s ansho), 11,67 (1H, s ansho) Example of Synthesis 9 N- (3 -Bromo-5-phenyl-lH-indol-7-yl) -5- siane-2-1-phenesulfonamide Under cooling are ice, sloro gas was introduced in a solids slurry syrup solution (15 ml) containing 1.3 g (5.6 mmol) of the dye of Produssion Example 30. After stirring for 30 minutes, the substitution solution was added. to ice-water and extracted are ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and consented. The residue was admised to a pyridine solution (6 ml) containing 1.2 g (5.35 mmol) of the mixture of Produssion Example 22, followed by agitation at room temperature during noshe. Water was added to it, and the mixture was extracted as ethyl acetate. The sap organelle was washed successively with 1 N slurryhydric acid, water and brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel, to give 1227 mg of the title compound. Melting point: 166 to 169 ° C (desomposition) ^ -NRM (DMSO-de) d (ppm): 2.30 (3H, s), 6.65 (1H, s), 7.07 (1H, s) ), 7.44 (1H, s), 7.54 (1H, d, J = 4.0 Hz), 7.94 (1H, d, J = 4.0 Hz), 10.47 (1H, s ansho), 11.04 (1H, s ansho) Synthesis Example 10 N- (4-B | romo-3-sloro-lH-indol-7-yl) -2- amino-5-pyrimidinesulfonamide 513 mg (2.65 mmol) of the title of Produssion Example 35 were added to 5 ml of a pyridine solution containing 712 mg (2.52 mmol) of the title of Produssion Example 34, followed by stirring for 15 hours. Water was added to the reassumption solution, and it was extracted in a mixture of ethyl acetate and tetrahydrofuran. (10: 1) The sap organza was blended on magnesium sulfate and then sonsented. The residue was purified by chromatography on silica gel solnum, to give 950 mg of the title suspension. Melting point: 285 to 289 ° C XH-NMR (DMSO-de) d (ppm): 6.75 (1H, d, J = 8.0 Hz), 7.19 (1H, d, J = 8, 0 Hz), 7.59 (1H, d, J = 3.0 Hz), 7.65 (2H, s), 8.37 (2H, s), 9.82 (1H, s), 11.43 (1H, s) Synthesis Example 11 N- (3-Chloro-lH-indol-7-yl) -4-sulfamoylbensenosulfonamide They were reassessed 767 mg (3.0 mmol) of 4-sulfamoylbensenosulfonyl sluride are 264 mg (2.0 mmol) of 7-amino-1H-indole, to give 445 mg of N- (1H-indol-7-yl) ) -4-Sulfanoylbensenosulfonamide. The resulting composition was slurried using N-slorosussinimide in dichloromethane to give 349 mg of the title compound. Melting point: it was only parsially soldered in black solor at a temperature close to 220 ° C and gradually decomposed at a temperature close to 240 ° C (recrystallized from ethanol-n-hexane). XH-NMR (DMSO-dg) d (ppm): 6.75 (1H, d, J = 7.6 Hz), 6.96 (1H, dd, J = 8.0, 7.6 Hz), 7 , 29 (1H, d, J = 7.6 Hz), 7.50 (1H, d, J = 2.8 Hz), 7.58 (2H, s), 7.90-7.98 (4H, m), 10.23 (1H, s), 11.07-11.17 (1H, m) Produssion Example 7-Bromo-1H-indole 100 ml (100 mmol) of a tetrahydrofuran solution containing bromide was added. of 1.0 M vinylmagnesium to a tetrahydrofuran solution (250 ml) containing 5.05 g (25 mmol) of 2-bromonitrobensen at -0 ° C under a nitrogen atmosphere, followed by stirring, for 40 minutes. The reaction mixture was poured into 500 ml of an asuous saturated solution of ammonium slurry, and the mixture was extracted with ethyl ether. The extra was blended on magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 2.89 g of the title compound. XH-NMR (DMSO-de) d (ppm): 6.56 (1H, dd, J = 2.9, 1.8 Hz), 6.94 (1H, t, J = 7.8 Hz), 7 , 30 (1H, d, J = 7.8 Hz), 7.40 (1H, t, J = 2.9 Hz), 7.56 (1H, d, J = 7.8 Hz), 11.16 -11.46 (1H, m ansho) Produssion Example 2a 7-Amino-1H-indole 16.5 ml (41.3 mmol) of a hexane solution containing 2.5 M n-butyllithium was dropwise added dropwise. Dissolve tetrahydrofuran (50 ml) with 2.70 g (13.8 mmol) of Produssion Example being stirred at -70 ° C under a nitrogen atmosphere, and the mixture was stirred at -70 ° C for 15 minutes and at -20 to -10 ° C for 30 minutes. After cooling to -70 ° C again, 3.9 ml (18 mmol) of diphenylphosphoryl azide was dropwise added. The mixture was stirred at -70 ° C for one hour and then at -40 ° C for one hour. After the addition of 22.3 ml (75.8 mmol) of a toluene solution containing bis (2-methoxyethoxy) aluminum hydride and sodium 3.4 M at -40 ° C, the mixture was stirred from -30 to -20. ° C for 30 minutes and then at room temperature for 30 minutes. A buffer solution of phosphorous acid having a pH of 7.0 was added, the insoluble products were filtered off and the filtrate was extracted with ethyl ether. The sapa organelle was washed sucsessively, it is a saturated aqueous solution of sodium bicarbonate and brine, it was blended on magnesium sulfate and was soncentrated. Then, the residue was purified by chromatography on silica gel solder, to give 1. 29 g of the title package. XH-NMR (DMSO-de) d (ppm): 5.01 (2H, s ansho), 6.25-6.33 (2H, m), 6.70 (1H, dd, J = 7.9, 7.3 Hz), 6.78 (1H, dd, J = 7.9, 0.7 Hz), 7.23 (1H, t, J = 2.7 Hz), 10.48-10.72 ( 1H, m ansho) The following starting compounds were synthesized from 2-bromonitrobenzene derivatives in the same manner as in Production Examples la and 2a. 7-amino-4-methoxy-1H-indole 7-amino-4-bromo-1H-indole Produssion Example 3a 7-Bromo-3-sloro-4-methyl-1H-indole 4.0 g (30.0%) were added. 0 mmol) of N-slorosussinimide to a solvation of asetonitrile (250 ml) containing 5.8 g (27.6 mmol) of 7-bromo-4-methyl-1H-indole synthesized from 2-bromo-5-methylnitrobenside in the same manner as in Produssion Example la, followed by agitation at room temperature during noshe. 50 ml of a 1N sodium hydroxide solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and consented. Then, the residue was purified by chromatography on silica gel solnum, to give 6.7 g of the title compound. XH-NMR (CDC13) d (ppm): 2.74 (3H, s), 6.75-7.26 (3H, m), 8.23 (1H, s ansho) Produssion Example 4a 7-Amino- 3-sloro-4-methyl-lH-indole 2.6 g of the title compound was obtained from 6. 37 g (26.1 mmol) of the dye of Produssion Example 3a d < ?! |? Just as in Produssion Example 2a. XH-NMR (CDCl3) d (ppm): 2.70 (3H, s), 6.39-7.14 (3H, m), 8.15 (1H, s ansho) Produssion Example 5a Chloride of 4- Sulfamoylbensenosulfonyl 6.4 g (37.2 mmol) of 4-aminobensenosulfonamide were added to a mixture of 12.5 ml of water and 6.3 ml of solid slurry dichloride, followed by agitation. A saturated aqueous solution containing 2.56 g (37.1 mmol) of sodium nitrite was added dropwise at 0 ° C or less. The reaction solution was admised to a dissolution in acid sulfur dioxide (dissolving obtained by saturation of 35 ml of solid acetic acid are sulfur dioxide and then 1.5 g of slurry-priso-dihydrate were added) under cooling They are ice are agitation. After 10 minutes, the reaction solution was poured over ice water, and the presipitated ones were resuscitated by filtration and washed are water. The presipitated ones were dissolved in tetrahydrofuran, sessed over magnesium sulfate and en-tonses were sonsented to dryness, to give 3.5 g of the title substance. Produssion Example 6a 4- (Sulfamoylmethyl) -bensenosulfonyl chloride 5.0 g (23.1 mmol) of 4-nitrophenylmethanesulfonamide was suspended in 90% acetic acid, then hydrogenated at normal temperature under normal pressure in pre-sensing palladium-sarbono After removing the satallizer by filtration, the filtrate was sonicated to dryness, to give 4.3 g of 4-aminophenylmethanesulfonamide. The obtained sommelium was admixed with a mixture of 40 ml of water and 4.1 ml of solid slurry dichloride, followed by agitation. A saturated aqueous solution containing 0.63 g (23.6 mmol) of sodium nitrite was added dropwise at 0 ° C or less. The reaction solution was admised to a solution in acetic acid are sulfur dioxide (dissolution obtained by saturation of 30 ml of solid acetic acid are sulfur dioxide and then 0.97 g of slurry superoxide dihydrate was added) under cooling They are ice are agitation. After stirring at room temperature for 40 minutes, the reaction solution was poured onto ice-water and the mixture was saturated with sodium slurium. The mixture was extracted with ethyl acetate, and the extract was dried over magnesium sulfate and then concentrated to dryness, to give 1.7 g of the title compound. XH-NMR (DMSO-de) d (ppm): 4.26 (2H, s), 7.32 (2H, d, J = 8.4 Hz), 7.59 (2H, d, J = 8, 4 Hz) The following blanks were synthesized in the same manner as in Produssion Example 5a or 6a. 4- (N-Methylsulfamoyl) Bensenosulfonyl Sluride 4- (N-Ethylsulfamoyl) Bensenosulfonyl Sluride 4- (N-Methoxysulfamoyl) Bensenosulfonyl Sluride 4- [(Methanesulfonamide) Methyl] Benzenesulfonyl Chloride 4- (N-Methylmethanesulfonamide) Chloride Benzenesulfonyl 4- (1-pyrrolidinylsulfonyl) benzenesulfonyl chloride 4- (1-pyrrolidinyl-arbonyl) -bensenosulfonyl sluride 3-siabensenosulfonyl sluride 4- (methylsulfonyl) bensenosulfonyl sluride 4- [(N-methylmethanesulfonamide) methyl] bensenosulphonyl chloride Example Produssion 7a 3-Cyano-7-nitro-1H-indole 10.15 g (53.4 mmol) of 3-formyl-7-nitro-1H-indole were dissolved in 150 ml of dimethylformamide, and 3 were added, 93 g (56.0 mmol) of hydroxylamine hydrochloride and 4.5 ml (55.6 mmol) of pyridine. After salting out they are agitated at 70 to 80 ° C for 2 hours, 6.3 g (56.8 mmol) of selenium dioxide and about 5 g of magnesium sulfate were added. After salting out at 70 to 80 ° C for 2.5 additional hours, they were removed by filtration Jajjaai .. ^.
The insoluble products and the filtrate were filtered. Water was adhered to it, and the resulting glazes were resuscitated by filtration and washed with water and ethyl ether. The crystals were dissolved in a solids mixture of tetrahydrofuran and asketone, and the insoluble products were removed by filtration. After showing the filtering, ethyl acetate was added to the residue and the crystals were sieved by filtration, to give 8.61 g of the title substance. XH-NMR (DMSO-de) d (ppm): 7.48 (1H, t, J = 8.1 Hz), 8.17 (1H, d, J = 8.1 Hz), 8.27 (1H , d, J = 8.1 Hz), 8.47 (1H, s), 12.70-13.00 (1H, ansha) Produssion Example 8a 7-Amino-3-sia-lH-indole 2 were suspended , 80 g (15.0 mmol) of the title of Production Example 7a in 100 ml of methanol and hydrogenated under normal pressure at normal temperature in the presence of palladium-carbon. After removing the catalyst by filtration, the reaction mixture was sonsented to dryness to give 2.31 g of the title compound. XH-NMR (DMSO-de) d (ppm): 5.32, 5.34 (2H, s + s), 6.47 (1H, d, J = 7.5 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.94 (1H, dd, J = 7.9, 7.5 Hz), 8.13 (1H, s), 11.55-11.90 (1H, ansha ), Example of Produssión 9a 7-Amino-3, 4-disloro-lH-indole The 7-bromo-4-sloro-lH-indole obtained from 2-bromo-5-sloronitrobenseno in the same way as in the Example Produssion was first sliced in the same manner as in Produssion Example 3a, and then the bromine group was converted into an amino group, to give the title substance. XH-NMR (DMSO-de) d (ppm): 5.26 (2H, s), 6.29 (1H, d, J = 8.1 Hz), 6.74 (1H, d, J = 8, 1 Hz), 7.45-7.51 (1H, m), 11.08-11.27 (1H, m) 7-amino-4-ters-butyldimethylsilyloxy-3-sloro-lH-indole was synthesized from the same way.
Produssion Example 10a 7-Amino-3-sloro-lH-indole 1.076 g (6.64 mmol) of 7-nitro-1H-indole was dissolved in 30 ml of asetonitrile, and 920 mg (6.89 mmol) were added. ) of N-slorosussinimide. After stirring at room temperature for 36 hours, a saturated aqueous solution of sodium bicarbonate was added. The precipitates were resuspended by filtration and washed are water, to give 1.2 g of 3-sloro-7-nitro-lH-indole. 863 mg (4.39 mmol) of the powder was suspended in 10 ml of ethanol, and 4.95 g (21.9 mmol) of stannous slurry • dihydrate and 100 μl of solid slurry dichloride were added. After refluxing for 30 minutes, a saturated sodium bicarbonate dissolution was added and the insoluble products were filtered out. After extracting by adduction of ethyl acetate, the extra was blended on magnesium sulfate and filtered. The residue was purified by chromatography in silica gel solnum, to give 490 mg of the title substance. The title compound was also obtained by hydrogenation of 3-sloro-7-nitro-lH-indole at normal temperature under normal pressure in the presence of a platinum-sarbonate satallizer. XH-NMR (DMSO-de) d (ppm): 5.14 (2H, s), 6.36 (1H, dd, J = 7.5, 1.0 Hz), 6.68 (1H, dd, J = 7.9, 0.73 Hz), 6.81 (1H, dd, J = 7.9, 7.5 Hz), 7.39 (1H, d, J = 2.7 Hz), 10, 85 (1H, s ansho) Produssion Example 4- (2-Sulfamoylethyl) -bensenosulfonyl chloride 1.3 g (7.3 mmol) of 2-phenylethanesulfonamide were added to 2.4 g (36.5 mmol) of solid slorosulphonium under cooling. ice for 20 minutes, followed by agitation at room temperature for an additional 90 minutes. The solder of the reassessing mixture was poured into ice-water, and then extracted is ethyl acetate. The extra was washed suc- cessively is a saturated dissolution of sodium bisarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, to give 1.6 g of the title compound. XH-NMR (DMSO-d6) d (ppm): 2.97-3.02 (2H, m), 3.21-3.26 (2H, m), 7.21 (2H, d, J = 8 , 4 Hz), 7.53 (2H, d, J = 8.4 Hz) The following raw materials were synthesized in the same manner. slurry of 4- [2- (methylsulfonyl) ethyl] bensenosulfonyl slurry of 4- [2- (N-methylmethanesulfonamide) ethyl] bensenosul-fonyl sluride of 4- [2- (methanesulfonamido) ethyl] bensenosulfonyl sluride of 4- (N- methylasetamido) bensenosulfonyl Produssion Example 12a 5-Bromo-7-nitro-lH-indole 5.05 g (17.7 mmol) of l-asethyl-5-bromo-7-nitroindoline was dissolved in a 6 ml mixed solution of ethanol and 40 ml of anhydrous 6N slurry, followed by refluxing for 3 hours. After neutralizing by adduction of sodium sarbonate, the mixture is extracted are ethyl acetate. The extra was washed is water, blended on magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solvate, to give 4.13 g of 5-bromo-7-nitroindoline. 301 mg (1.24 mmol) of this compound were added to 10 ml of toluene, and then 580 mg (2.55 mmol) of 2,3-disloro-5,6-di-1,4-benzoquinone were added thereto. . After refluxing for 3.5 hours while stirring, the insoluble products were removed by filtration and the filtrate was filtered. The residue was purified by chromatography on silica gel solnum, to give 252 mg of the title compound. Produssion Example 13a 5-Bromo-3-formyl-7-nitro-1H-indole 210 mg (1.4 mmol) of phosphorus oxychloride was added to 1.0 g (14 mmol) of dimethylformamide at 0 ° C in an atmosphere of nitrogen, followed by agitation for 30 minutes. 240 mg (1.0 mmol) of the suspension of Produssion Example 12a were added at 0 ° C, and the mixture was stirred at 0 ° C for 20 minutes and then at 100 ° C for 30 minutes. The reassuring mixture cooled down to ice and then poured into ice-water. The mixture was stirred for 30 minutes, while maintaining pH 7 to 8 by the addition of a sodium hydroxide solution. The resulting presipitate was respected by filtration, it was washed, and then it was purified by chromatography on silica gel solnum, to give 239 mg of the title substance. XH-NMR (DMSO-de) d (ppm): 8.31 (1H, d, J = 1.8 Hz), 8.55 (1H, s), 8.65 (1H, d, J = 1, 8 Hz), 10.05 (1H, s), 12.89 (1H, s ansho) Produssion Example 14a 7-Amino-5-bromo-3-sia-lH-indole 214 mg (0.8 mmol. ) of 5-bromo-3-siane-7-nitro-1H-indole obtained from the dye of Produssion Example 13a in the same manner as in Produssion Example 7a, in a mixed solution of 10 ml of methanol and ml of tetrahydrofuran. The mixture was hydrogenated at 3.0 kg / sm in platinum oxide presensia, then the catalyst was removed by filtration and the filtrate was dried to dryness, to give 189 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 5.68-5.71 (2H, m), 6.60 (1H, d, J = 2.0 Hz), 6.91 (1H, d, J = 2.0 Hz), 8.16 (1H, s) Production Example 15a 3-Asethyl-7-amino-1H-indole 11 ml (11 mmol) of a hexane solution containing dimethylaluminum 1 slurry was added. 0 M to a solution in dichloromethane (50 ml) containing 1.2 g (7.5 mmol) of 7-nitro-1H-indole at 0 ° C under a nitrogen atmosphere. Then, 2.1 ml (29.5 mmol) of asystulide slurry was added at 0 ° C, followed by stirring at room temperature for 4 hours. A saturated saturated dissolution of ammonium slurry was adhered to the reassessment system and the resultant presipitate was resuscitated by filtration. These presipitados washed suficiently are outgoing ethanol. The dissolution of "*** t * ^ tt? r." «? ¡m ** - ^. ^. ^. i ^. ^ iiiMy wash was called the filtrate and the combined sol- lution was shown, water was added to the residue, and The mixture is extracted with ethyl acetate, the extra is washed with brine, and the solution is magnesium sulfate, the solvent is evaporated and the residue is purified by chromatography on silica gel solvate to give 3-asethyl-7. -nitro-lH-indole The prodrug was dissolved in 100 ml of methanol and hydrogenated at normal temperature under normal pressure in palladium-sarbon presensia.After removing the sachallizer by filtration, the filtrate was dried to dryness to give 790 mg of the title compound Example of Synthesis N- (lH-Indol-7-yl) -4-nitrobenzenesul-fonamide 1.50 g (11.3 mmol) of the dye of Produssion Example 2a was dissolved in 40 ml of pyridine, followed by the addition of 2.57 g (11.6 mmol) of 4-nitrobensenosulfonyl slurry at room temperature, stirring. At room temperature overnight, the solvent was evaporated, and to the residue were added ethyl acetate and anhydrous 0.2 N slurry. The sap organelle was separated, washed with water, slurried over magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by chromatography on silica gel solnum, to give 3.50 g of the title compound. H-NMR (DMSO-ds) d (ppm): 6.42 (1H, dd, J = 2.8, 2.0 Hz), 6.66 (1H, d, J = 7.6 Hz), 6 , 83 (1H, dd, J = 8.0, 7.6 Hz), 7.31 (1H, dd, J = 3.2, 2.8 Hz), 7.36 (1H, d, J = 8 , 0 Hz), 7.94-8.02 (2H, m), 8.30-8.38 (2H, m), 10.23 (1H, s), 10.74-10.87 (1H, m) Synthesis Example 2a N- (3-Chloro-lH-indol-7-yl) -4-nitro-ben-senosulfonamide 8.98 g (28.3 mmol) of the composition of Synthesis Example la was dissolved in a solosion of 280 ml of dichloromethane and 7 ml of dimethylformamide, followed by the addition of 4.16 g (31.2 mmol) of N-slorosussinimide are agitated under nitrogen atmosphere. After stirring at room temperature for 1.5 hours, 50 ml of water was added and the mixture was sonsented until the sanctity of the mixture became approximately 80 ml. The organic sap was separated by adduction of ethyl acetate and anhydrous 0.2 N slurry, washed supersively, saturated aqueous sodium bicarbonate solution and brine, and brazed on magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by chromatography on silica gel solnum, to give 7.98 g of the title compound. Melting point: 199.5 to 200, 5 ° C (recrystallized from sloroformo) XH-NMR (DMSO-de) d (ppm): 6.72 (1H, d, J = 7.6 Hz), 6 , 96 (1H, dd, J = 8.0, 7.6 Hz), 7.31 (1H, d, J = 8.0 Hz), 7.47-7.53 (1H, m), 7, 92-8.02 (2H, m), 8.30-8.41 (2H, m), 10.33 (1H, s), 11.07-11.22 (1H, m) Synthesis Example 3a 4 -Amino-N- (3-sloro-lH-indol-7-yl) bensenosulfonamide 7.98 g (22.7 mmol) of the somatum of Synthesis Example 2a were dissolved in 220 ml of methanol, followed by refluxing are agitation 10 ml of dry sulfur dioxide and 7.40 g of powdered sins were added three times at 10 minute intervals, followed by reflux for 10 additional minutes. After cooling, the reassessing mixture was neutralized by adduction of a significant excess of sodium bisarbonate and the insoluble products were removed by filtration. After showing the filtrate, the residue was dissolved in ethyl acetate. The mixture was thoroughly washed, a saturated aqueous solution of sodium bisarbonate, a 2N aqueous solution of sodium sarbonate and brine, dried over magnesium sulfate, and then the solvent was evaporated. The residue was purified by chromatography on silica gel solnum to give 7.21 g of the title compound.
Melting point: 174.5 to 176 ° C (resistastalised from ethanol-n-hexane) XH-NMR (DMSO-de) d (ppm): 5.97 (2H, s ansho), 6.48 (2H, d) , J-8.8 Hz), 6.88 (1H, d, J = 7.6 Hz), 6.95 (1H, dd, J = 8.0, 7.6 Hz), 7.19 (1H , d, J = 8.0 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.46 (1H, d, J = 2.4 Hz), 9.56 (1H, s), 10.86-10.98 (1H, m) Synthesis Example 4a N- (3-Chloro-1H-indol-7-yl) ) -4- (methanesulfonamide) bensenosulfonamide 68 mg (0.211 mmol) of the somatum of Synthesis Example 3a was dissolved in 1 ml of pyridine, followed by the addition of 15 μl (0.194 mmol) of methanesulfonyl slurry. After stirring at room temperature during noshe, an asuous dissolution of sodium bisarbonate was added, and the mixture was extracted with ethyl acetate. The organic sap was washed sucsively are diluted slorhídriso and water, was blended on magnesium sulfate, and sonsentro. Then, the residue was purified by chromatography in a thin layer of silica gel, to give 76 mg of the title substance. Melting point: 213.5 to 214 ° C (desomposition) (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 3.08 (3H, s), 6.83 (1H, d, J = 7.5 Hz), 6.96 (1H, dd, J = 7.9, 7.7 Hz), 7.23 (2H, d, J = 8.8 Hz), 7 , 24 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.68 (2H, d, J = 8.8 Hz), 9.92 (1H, s ansho), 10.38 (1H, s ansho), 10.99 (1H, s ansho) Synthesis Example 5a 4 -Bromomethyl-N- (lH-indol-7-yl) bensenosulfonamide They were reassessed 4-bromomethyl-bensenosulfonyl sloride and the compound of Produssion Example 2a in tetrahydrofuran at room temperature in presensia of one molar equivalent of pyridine and treated in the same manner as in Synthesis Example lam, to give the title compound. XH-NMR (DMSO-de) (ppm): 4.70 (2H, s), 6.40 (1H, dd, J = 3.1, 1.1 Hz), 6.71 (1H, ddd, J = 7.4, 3.2, 0.92 Hz), 6.81 (1H, ddd, J = 8.1, 7.4, 0.92 Hz), 7.29-7.32 (2H, m ), 7.57 (2H, d, J = 8.2 Hz), 7.73 (2H, d, J = 8.4 Hz), 9.96 (1H, s ansho), 10.75 (1H, s ansho) Synthesis Example 6a N- (1, 3-Dihydro-2H-indol-2-a-7-yl) -4-methylbensenosulfonamide The title was obtained in the same manner as in Synthesis Example la. Melting point: gradually melting at a temperature close to 246 ° C and rapidly decomposing from 267 to 269 ° C (resrystallized from dioxane). Synthesis Example 7a 3-Chloro-N- (3-sloro-lH-indol-7-yl) bensenosulfonamide 2.18 g (7.11 mmol) of 3-sloro-N- (lH-ind? L- 7-yl) bensenosulfonamide synthesized in the same manner as in Synthesis Example la, in the same manner as in Example 2a, to give 1.86 g of the title compound. Melting point: 180 to 181 ° C (recrystallized from dichloromethane / diisopropyl ether) ^ -NRM (DMSO-de) d (ppm): 6.73 (1H, d, J = 7.6 Hz), 6, 97 (1H, dd, J = 8.0, 7.6 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.45-7.51 (1H, m), 7.51 -7.76 (4H, m), 10.09 (1H, s), 11.02-11.18 (1H, m) Synthesis Example 8a 4-Amino-N- (3, 4-disloro-lH- indol-7-yl) bensenosulfonamide 2.03 g of the title compound was obtained from 2.43 g (6.29 mmol) of N- (3,4-disloro-lH-indol-7-yl) -4 -nitrobensenosulfonamide synthesized in the same manner as in Synthesis Example la, in the same manner as in Example 3a. Melting point: 205 to 206, 5 ° C (desomposition) (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.00 (2H, s), 6.50 (2H , d, J = 8.4 Hz), 6.77 (1H, d, J = 8.0 Hz), 6.94 (1H, d, J = 8.0 Hz), 7.35 (2H, d , J = 8.4 Hz), 7.51-7.58 (1H, m), 9.57 (1H, s), 11.20- "• * -" -fitilliliiHi 11.38 (1H, m) Synthesis Example 9a Asid 4- [N- (lH-Indol-7-yl) sulfamoyl] -benzoiso The title was obtained in the same way as in the Synthesis Example la. ^ -NMR (DMSO-de) d (ppm): 6.40 (1H, dd, J = 2.9, 1.9 Hz), 6.67 (1H, d, J = 7.5 Hz), 6 , 82 (1H, dd, J = 7.9, 7.5 Hz), 7.31 (1H, dd, J = 2.9, 2.7 Hz), 7.33 (1H, d, J = 7 , 9 Hz), 7.81-7.88 (2H, m), 7.99-8.07 (2H, m), 10.07 (1H, s), 10.73-10.83 (1H, m), 13.30-13.58 (1H, ansha) Synthesis Example 10a N- (3-Chloro-1H-indol-7-yl) -4-sianoben-senosulfonamide 76 mg of the title compound was obtained. same as in Example 2a, from 100 mg of 4-siane-N- (lH-indol-7-yl) bensenosulfonamide synthesized in the same manner as in Synthesis Example la. Melting point: 210 to 211 ° C (recrystallized from ethyl acetate / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.71 (1H, dd, J = 7.6, 0.8 Hz), 6, 96 (1H, dd, J = 8.0, 7.6 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.48 (1H, dd, J = 2 , 4, 0.8 Hz), 7.82-7.90 (2H, m), 7.97-8.05 (2H, m), 10.25 (1H, s), 11.04-11.15 (1H, m) Synthesis Example lia 3-Chloro-N- (3-sloro-4-hydroxy-lH-indol-7-yl) bensenosulfonamide obtained 52 mg of the title compound in the same manner as in Example 2a, from 100 mg of 3-sloro-N- (4-methoxy-lH-indol-7-yl) bensenosulfonamide synthesized in the same manner as in the Example of Synthesis la. ^ -NMR (DMSO-de) d (ppm): 3.79 (3H, s), 6.37 (1H, d, J = 8.4 Hz), 6.45 (1H, d, J = 8, 4 Hz), 7.24-7.31 (1H, m), 7.48-7.77 (4H, m), 9.76 (1H, s), 11.06-11.17 (1H, m) Synthesis Example 12a 3-Chloro-N- (3-sloro-4-hydroxy-1H-indole) 7-yl) bensenosulfonamide 220 mg (0.47 mmol) of N- (4-tert-butyl- '.z' "'' -> thiomethyl) bensenosulfonamide 1.97 g (5.37 mmol) of the composition of Synthesis Example 5a was dissolved in 10 ml of tetrahydrofuran, 10 ml (39.4 ml) were added to the mixture. mmol) of a 15% sodium methylthiolate asoluous dissolution and a catholic sanity, of methyltriostylammonium slurry at room temperature, followed by stirring during the noshe, 20 ml of water were added, and the mixture was extracted. The ethyl acetate was washed, the organics were washed with water, dried over magnesium sulfate and sonsented, and the residue was purified by chromatography on silica gel solvate to give 1.51 g of N- (1H-indole). -7-yl) -4- (methylthiomethyl) bensenosulfonamide The prodrug was slurried in the same manner as in Example 2a to give 839 mg of the title compound XH-NMR (DMSO-d6) d (ppm): 1 , 87 (3H, s), 3.70 (2H, s), 6.77 (1H, dd, J = 7.6, 2.1 Hz), 6.94 (1H, dd, J = 7.9 , 7.7 Hz), 7.24 (1H, d, J = 7.9 Hz), 7.42 (2H, d, J = 8.2 Hz), 7 , 47 (1H, d, J * 2.6 Hz), 7.67 (2H, d, J = 8.4 Hz), 9.96 (1H, s ansho), 11.01 (1H, s ansho) Synthesis Example 16a 3-Chloro-N- (3-formyl-lH-indol-7-yl) bensenosulfonamide 1.3 ml (13.9 mmol) of phosphorus oxychloride 14.5 ml of dimethylformamide were dropwise added dropwise. 10 ° C or less are agitation, under a nitrogen atmosphere. After stirring at about 5 ° C for 30 minutes, 2.50 g (8.15 mmol) of 3-sloro-N- (lH-indol-7-yl) bensenosulfonamide synthesized in the same manner as in the Example 1 in three sections. After stirring at about 5 ° C for 30 additional minutes, 200 ml of cold water was added. The reaction mixture was adjusted to approximately pH 14 by adduction of a sodium hydroxide solution IN and then to pH approximately 2 by the addition of an inorganic slurry, and then extracted by ethyl acetate addition. The sapa orgánisa was washed are brine, It was dried over magnesium sulfate and filtered. The residue was purified by chromatography in silica gel solnum, to give 1.45 g of the title compound. ^ -NMR (DMSO-d6) d (ppm): 6.70 (1H, dd, J = 7.6, 0.8 Hz), 7.06 (1H, dd, J = 8.0, 7.6 Hz), 7.51-7.75 (4H, m), 7.93 (1H, d, J = 8.0 Hz), 8.22-8.28 (1H, m), 9.93 (1H , s), 10.17 (1H, s), 11.86-11, 98 (1H, m) Synthesis Example 17a 3-Chloro-N- (3-sia-lH-indol-7-yl) bensenosulfonamide 274 mg (3.94 mmol) of hydroxylamine hydrosulfate and 0.32 ml were added. (3.96 mmol) of pyridine to a dissolution of dimethylformamide (18 ml) by stirring 1.20 g (3.58 mmol) of the suspension of Synthesis Example 16a from 70 to 80 ° C are stirred. After stirring for 2.5 hours under sodium, 437 mg (3.94 mmol) of selenium dioxide and approximately 100 mg of powdered magnesium sulfate were added. After stirring at the same temperature for 2 additional hours, the solvent was evaporated. The ethyl acetate residue was admised, and the insoluble products were filtered off. The filtrate was washed successively with 0.1 N hydrochloric acid and brine, dried over magnesium sulfate and the solvent was evaporated. The residue was purified by chromatography on silica gel solvate to give 678 mg of the title suspension. Melting point: 204.5 to 205 ° C (recrystallized from ethyl acetate / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.71 (1H, d, J = 7.6 Hz) , 7.08 (1H, dd, J = 8.0, 7.6 Hz), 7.47 (1H, d, J = 8.0 Hz), 7.50-7.76 (4H, m), 8.17-8.25 (1H, m), 10.21 (1H, s), 11.92-12.09 (1H, ra) Synthesis Example 18a 6-Chloro-N- (3-sia-lH) -indol-7-yl) -3- pyridinesulfonamide The title was obtained in the same manner as in Synthesis Example la. ^ -NMR (DMSO-de) d (ppm): 6.77 (1H, d, J = 7.9 Hz), 7.12 (1H, t, J = 7.9 Hz), 7.50 (1H, d, J = 7.9 Hz), 7.72 (1H, d, J = 8.4 Hz), 8.06 (1H, dd, J = 8.4, 2.6 Hz), 8.23 (1H, d, J = 2.6 Hz), 8.65 (1H, d, J = 2.6 Hz), 10.34-10, 48 (1H, ansha), 11.98-12.12 (1H, m) Synthesis Example 19a N- (3-Chloro-lH-indol-7-yl) -4-sulphaoylbensenosulfonamide. 767 mg were reactivated ( 3.0 mmol) of the suspension of Produssion Example 5a and 264 mg (2.0 mmol) of the compound of Produssion Example 2a and were treated in the same manner as in Example la, to give 445 mg of N- (lH-indol-7- il) -4-sulfamoylbensenosulfonamide. The prodrug was sliced in the same manner as in Example 2a, to give 349 mg of the title substance. Melting point: it was only parsially soldered in black solor at a temperature close to 220 ° C and gradually disentangled at a temperature close to 240 ° C (recrystallized from ethanol / n-hexane). ^ -RM (DMSO-de) d (ppm): 6.75 (1H, d, J = 7.6 Hz), 6.96 (1H, dd, J = 8.0, 7.6 Hz), 7 , 29 (1H, d, J = 7.6 Hz), 7.50 (1H, d, J = 2.8 Hz), 7.58 (2H, s), 7.90-7.98 (4H, m), 10.23 (1H, s), 11.07-11.17 (1H, m) Synthesis Example 20a 3-Sloro-N- (8-imidazo [1,2-a] pyridinyl) bensenosulfonamide hydrochloride 1.97 g (18 mmol) of 2,3-d-aminopyridine were dissolved in a mixture mixture of tetrahydrofuran and water, and a tetrahydrofuran solution was added containing 1.90 g (9.0 mmol) of slurry of 3 g. -solobensenosulfonyl. After stirring at room temperature during noshe, the mixture was filtered, and water and dichloromethane were adhered to the residue. The sapa organelle was separated, and the wall of the reastor was reopened as sausho. The resulting crystals were reslurried by filtration, to give 1.41 g of N- (2-amino-3-pyridinyl) -3-slorobensenosulfonamide. 530 mg (1.87 mmol) of the crystals were dissolved in methanol and 367 mg (1.87 mmol) were added. mmol) of a dissoluting asuosa to 40% of sloro asetoaldehyde. After refluxing for 4 hours, the mixture was dried to dryness. A small holiness of methanol was added to the residue and the crystals were filtered by filtration to give 373 mg of the title substance. Melting point: gradual deposition from a temperature close to 210 ° C (recrystallized from ethanol) Synthesis Example 21a N- (3,4-Dichloro-lH-indol-7-yl) -4-sulfamoylbensenosulfonamide They were reassumed 429 mg (1.68 mmol) of the title of Produssion Example 5a and 250 mg (1.24 mmol) of the dye of Produssion Example 9a and treated in the same manner as in Example la, to give 200 mg of the title compound. Title. Melting point: melting at a temperature close to 282 ° C and gradual desomposition (recrystallized from ethanol / ethyl ether). XH-NMR (DMSO-d6) d (ppm): 6.62 (1H, d, J = 8.1 Hz), 6.95 (1H, d, J = 8.1 Hz), 7.53-7 , 62 (3H, m), 7.87-7.99 (4H, m), 10.17-10.33 (1H, ansha), 11.44-11.56 (1H, m) Synthesis Example 22a N- (3-Chloro-lH-indol-7-yl) -4- (methylthio) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. ^ -NMR (DMSO-de) d (ppm): 2.48 (3H, s), 6.82 (1H, dd, J = 7.9, 1.5 Hz), 6.96 (1H, dd, J = 8.1, 7.5 Hz), 7.25 (1H, dd, J = 7.9, 0.92 Hz), 7.33 (2H, d, J = 8.8 Hz), 7, 49 (1H, d, J = 2.7 Hz), 7.62 (2H, d, J = 8.6 Hz), 9.96 (1H, s ansho), 11.02 (1H, s ansho) Example Synthesis 23a N- (3-Chloro-lH-indol-7-yl) -4- (methylsulfonyl) bensenosulfonamide 54.2 mg (0.154 mmol) of the somatic compound of Synthesis Example 22a was dissolved in a 2 ml mixed solution of methanol and 1.2 ml of water, this was then * * »* M * .. ^^ MlM XiK mg of ammonium molybdate-tetrahydrate and 0.6 ml of 30% hydrogen peroxide at room temperature. After shaking during noshe, water was added and the mixture was extracted with ethyl acetate. The extra was washed is water, blended on magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel solnum, to give 29.4 mg of the title substance. Melting point: melting at a temperature close to 250 ° C and dessomposing from 264 to 266 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 3, 28 (3H, s), 6.75 (1H, d, J = 7.7 Hz), 6.97 (1H, dd, J = 7.9, 7.7 Hz), 7.30 (1H, d, J = 8.1 Hz), 7.50 (1H, d, J = 2.7 Hz), 7.97 (2H, d, J = 8.2 Hz), 8.09 (2H, d, J = 8.4 Hz), 10.29 (1H, s ansho), 11.12 (1H, s ansho) Synthesis Example 24a N- (3-Chloro-lH-indol-7-yl) -4- ( methylsulfinyl) bensenosulfonamide 19.9 mg (0.056 mmol) of the suspension of Synthesis Example 22a were dissolved in 2 ml of dichloromethane, followed by addition of 10 mg (0.058 mmol) of m-sloroperbenzoate are agi-tation under cooling are ice. After one hour, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The extra was washed is water, blended on magnesium sulfate and filtered. Then, the residue was purified by chromatography on a thin sapphire gel, to give 14.4 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 2.76 (3H, s), 6.78 (1H, dd, J = 7.5, 1.1 Hz), 6.96 (1H, dt, Jd = 0.55 Hz, Jt = 7.8 Hz), 7.28 (1H, dd, J = 7.6, 0.82 Hz), 7.48 (1H, d, J = 2.7 Hz) , 7.82 (2H, d, J = 8.6 Hz), 7.89 (2H, d, J = 8.8 Hz), 10.15 (1H, s ansho), 11.06 (1H, s ansho) Synthesis Example 25a 3-Chloro-N- (3-sloro-lH-pyrrolo [3, 2-s] pyridin-7-yl) bensenosulfonamide The title was obtained in the same way as ntnii i .ftllli y p HJMMIÍ ü »,] a, lt ttltt iil *? m? ¡á? * ^ * in Synthesis Examples la and 2a. XH-NMR (DMSO-de) d (ppm): 7.41-7.65 (2H, m), 7.65-7.77 (2H, m), 7.74-7.86 (2H, m) ), 8.40-8.62 (1H, m ansho), 12.38-12.58 (1H, ansha), 13.56-13.74 (1H, ansha) Synthesis Example 26a 4-Asetamide-N - (3-sloro-4-methyl-lH-indol-7-yl) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Example la. Melting point: gradual deposition from a temperature close to 225 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 2.03 (3H, s), 2.56 (3H, s), 6.54-6.60 (2H, m), 7.33 (1H, d, J = 2.6 Hz), 7.60 (2H, d, J = 9.0 Hz) , 7.64 (2H, d, J = 9.0 Hz), 9.63 (1H, s ansho), 10.24 (1H, s ansho), 10.92 (1H, s ansho) Synthesis Example 27a 4-Amino-N- (3-sloro-4-phenyl-lH-indol-7-yl) bensenosulfonamide 3.75 g (9.9 mmol) of the suspension of Synthesis Example 26a was dissolved in 25 ml of an ashesy dissolution 2 N of sodium hydroxide, followed by agitation at 100 ° C for 2 hours. After returning to room temperature, the mixture was adjusted to pH 6 by adduction of acidic acetic acid. The resulting precipitate was collected by filtration and purified by chromatography on silica gel solnum to give 1.1 g of the title compound. Melting point: gradual deposition from a temperature close to 230 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-d6) d (ppm): 2.56 (3H, s), 5.93 (2H, s ansho), 6.46 (2H, d, J = 8.8 Hz), 6.59 (1H, d, J = 7.8 Hz), 6.64 (1H, d, J = 7 , 8 Hz), 7.31 (2H, d, J = 8.8 Hz), 7.36 (1H, d, J = 2.9 Hz), 9.34 (1H, s ansho), 10.88 (1H, s ansho) Synthesis Example 28a 4-Cyano-N- (3-sia-lH-indol-7-yl) bensenosulfonamide. The title was obtained in the same way as in the Synthesis Example la.
Melting point: 250.5 to 252 ° C (recrystallized from ethyl acetate / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.67 (1H, d, J = 7.7 Hz) , 7.05 (1H, t, J = 7.9 Hz), 7.44 (1H, d, J = 7.7 Hz), 7.78-7.87 (2H, m), 7.97- 8.05 (2H, m), 8.16-8.23 (1H, m), 10.28-10.43 (1H, ansha), 11.92-12.09 (1H, m) Synthesis Example 29a-Carbamoyl-N- (3-sloro-lH-indol-7-yl) bensenosulfonamide To a solution of 1.0 g (3.01 mmol) of the compound of Synthesis Example 10a adsorbed to 4.8 ml of ethanol , 2.4 ml of a 30% asoluous hydrogen peroxide dissolution was added and 360 μl of a 6 N asoluous dissolution of sodium hydroxide was added to the catalyst three times during stirring. (Reassurance temperature: 50 ° C approximately). After stirring at 50 ° C for 30 additional minutes, the reassessment mixture was assidulated by adsorption of dilute slurrydish acid and then extracted was ethyl acetate. The sapa organelle was resuscitated by frassing, washed with water, blended on magnesium sulfate and filtered. The residue was purified by chromatography on silica gel solnum, to give 600 mg of the title compound. Melting point: it starts to be quenched and dessomped from a temperature close to 248 ° C and quickly decomposes from 252.5 to 253.5 ° C (recrystallized from ethanol / n-hexane) ^ -RMN (DMSO-de) d (ppm): 6.76 (1H, d, J = 7.5 Hz), 6.95 (1H, dd, J = 8.1, 7.5 Hz), 7.27 (1H, d, J = 8.1 Hz), 7.49 (1H, d, J * 2.6 Hz), 7.59 (1H, s ansho), 7.76-7.83 (2H, m), 7.91-7 , 98 (2H, m), 8.12 (1H, s ansho), 10.10 (1H, s), 11.01-11.12 (1H, m) Synthesis Example 30a N- (4-Bromo- lH-indol-7-? l) -4-m-bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-de) d (ppm): 6.35-6.41 (1H, m), 6.56 (1H, d, J = 8.4 Hz), 7.06 (1H, dd, J = 8.4, 0.8 Hz), 7.41-7.48 (1H, m), 7.92-8.02 (2H, m ), 8.30-8.41 (2H, m), 10.34 (1H, s), 11.18-11.32 (1H, m) Synthesis Example 31a N- (3-Chloro-4-sial) -lH-indol-7-yl) -4- nitrobensenosulfonamide 200 mg (0.505 mmol) of the somatum of Synthesis Example 30a was dissolved in 0.8 ml of N-methylpyrrolidone, followed by an addition of 83 mg (0.degree., 91 mmol) of supiary sianide. After stirring at 180 to 190 ° C for 3 hours, 40 ml of ice-water were added. The insoluble products were resuscitated by filtration, water was washed, and outgoing ethanol and outgoing sloroform were extracted. The extractant was filtered and the residue was purified by thin-layer chromatography on silica gel, to give 65 mg of N- (4-sia-lH-indol-7-yl) -4-nitrobensenosulfonamide. This prodrug was sliced in the same manner as in Example 2, to give 42 mg of the title substance. ^ -NMR (DMSO-d6) d (ppm): 6.98 (1H, d, J = 8.0 Hz), 7.51 (1H, d, J = 8.0 Hz), 7.79 (1H , d, J = 2.8 Hz), 7.99-8.08 (2H, m), 8.31-8.40 (2H, m), 10.75-10.95 (1H, ansha), 11.62-11.73 (1H, m) Synthesis Example 32a 4-Amino-N- (3-sloro-4-sia-lH-indole-7-yl) bensenosulfonamide The title compound was obtained from the moiety of Synthesis Example 31a in the same manner as in Synthesis Example 3a. Melting point: desomposition takes place from a temperature close to 232 ° C and rapidly decomposes from 249.5 to 255 ° C (recrystallized from ethanol-n-hexane) XH-NMR (DMSO-de) d (ppm): 6.09 (2H, s), 6.52 (2H, d, J = 8.8 Hz), 7.10 (1H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 8.4 Hz), 7.72-7.79 (1H, m), 10.20 (1H, s), 11.40- 11 , 59 (1H, m) Synthesis Example 33a 6-Amino-N- (3-sloro-lH-indol-7-yl) -3- pyridinesulfonamide 2.48 g (7.25 mmol) of the suspension of Synthesis Example 14a and 679 mg (5.07 mmol) of lithium iodide were added to 25 ml of ethanol. 10 ml of liquid ammonia was added, and the mixture was heated at 120 ° C for 26 hours in a serrated tube and then sonsensed. The residue was dissolved in ethyl acetate, and the mixture washed successively is a saturated aqueous solution of sodium bisarbonate and water, brazed on magnesium sulfate and filtered. Intoleons, the residue was purified by chromatography on silica gel solnum, to give 982 mg of the title substance. Melting point: 206 to 207 ° C (recrystallized from ethyl-n-hexane) ^ -RMN (DMSO-d6) d (ppm): 6.37 (1H, d, J = 8.8 Hz), 6.83 -6.94 (1H, m), 6.88 (2H, s ansho), 6.99 (1H, dd, J = 7.9, 7.7 Hz), 7.25 (1H, dd, J = 7.9, 0.7 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.56 (1H, dd, J = 8.8, 2.4 Hz), 8.14 (1H, d, J = 2.4 Hz), 9.70 (1H, s), 10.92-11.03 ( 1H, m) Synthesis Example 34a N- (3-Chloro-lH-indol-7-yl) -4- (methyl-sulfinylmethyl) bensenosulfonamide The title compound was obtained by oxidation of the compound of Synthesis Example 15a thereof as in Example 24a. XH-NMR (DMSO-de) d (ppm): 2.41 (3H, s), 3.98 (1H, d, J = 12.6 Hz), 4.18 (1H, d, J = 12, 8 Hz), 6.77 (1H, d, J = 7.5 Hz), 6.94 (1H, dd, J = 7.9, 7.7 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.43 (2H, d, J = 8.1 Hz), 7 , 47 (1H, d, J = 2.8 Hz), 7.73 (2H, d, J = 8.1) Hz), 10.01 (1H, s ansho), 11.03 (1H, s ansho) Synthesis Example 35a N- (3-Chloro-lH-indol-7-yl) -4- (2-sulfamoylethyl) bensenosulfonamide 865 mg (3.05 mmol) of the title of Produsions Example were reassumed to 376 mg (2.84 mmol) of the title of Produssion Example 2a and treated in the same manner as in Example la. The 957 mg of N- (1H-) were lowered tt_, aa., *. ^.,? ^ AAI ^, aM ^ indole-7-yl) -4- (2-sulfamoylethyl) bensenosulfonamide resulting in the same manner as in Example 2a, to give 980 mg of the Title. Melting point: 217 to 219 ° C (desomposition) (recrystallized from ethanol-n-hexane) XH-R N (DMSO-de) d (ppm): 3.01-3.06 (2H, m), 3, 23-3.28 (2H, m), 6.81 (1H, dd, J = 7.5, 0.37 Hz), 6.88 (2H, s ansho), 6.95 (1H, dd, J = 8.1, 7.5 Hz), 7.24 (1H, dd, J = 7.8, 0.37 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.49 (1H, d, J = 2.6 Hz), 7.68 (2H, 10 d, J = 8.2 Hz), 9.99 (1H, s ansho), 11.02 (1H, s ansho) Synthesis Example 36a N- (3-Chloro-lH-indol-7-yl) - 4- [2- (Methylsulfonyl) ethyl] bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. 15 Melting point: melting at a temperature close to 180 ° C and decomposing at 201 to 203 ° C (recrystallized from ethanol-n-hexane) ^ -RMN (DMSO-de) d (ppm): 2.92 (3H , s), 3.01-3.07 (2H, m), 3.40-3.46 (2H, m), 6.81 (1H, d, J = 7.9 Hz), 6.94 ( 1H, dd, J = 20 7.9, 7.7 Hz), 7.24 (1H, d, J = 7.7 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.49 (1H, d , J = 2.7 Hz), 7.68 (2H, d, J = 8.2 Hz), 9.99 (1H, s ansho), 11.03 (1H, s ansho) Synthesis Example 37a 6- Amino-N- (3-sia-lH-indol-7-yl) -3-pyridinesulfonamide The somatum of Synthesis Example 18a was aired in the same manner as in Example 33a, to give the title compound. Melting point: 300 ° C or more (recrystallized from ethanol-n-hexane) 30 ^ -NMR (DMSO-de) d (ppm): 6.39 (1H, d, J = 9.0 Hz), 6, 88 (1H, d, J = 7.7 Hz), 6.89 (2H, s), 7.11 (1H, dd, J = 7.9, 7.7 Hz), 7.41 (1H, dd) , J = 7.9, 0.7 Hz), 7.55 (1H, dd, J = 9.0, 2.6 Hz), 8.12 (1H, d, J = 2.6 Hz), 8 , 19 (1H, s), 9.72-9.90 (1H, ansha), 11.78-11.92 (1H, m) , ^^^^^ ¡H. * «. ** HAÉH. «« A * ... ^^ ü • - "- ^" - A ^ -'- ^ Tflfjl.-fÉ ^ - ^^ a ^^ Example of Synthesis 38a 4-Asetamido-3-sloro-N- ( 3-sloro-lH-indol-7-yl) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. XH-NMR (DMSO-de) d (ppm): 2.14 (3H, s), 6.77 (1H, d, J = 7.7 Hz), 6.98 (1H, dd, J = 7, 9, 7.7 Hz), 7.29 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = 2.7 Hz), 7.64 (1H, dd, J = 8.6, 2.2 Hz), 7.75 (1H, d, J = 2.2 Hz), 8.04 (1H, d, J = 8.6 Hz), 9.69 (1H, s ansho ), 10.04 (1H, s ansho), 11.11 (1H, s ansho) Synthesis Example 39a N- (3-siane-lH-indol-7-yl) -8-guignolinesulfonamide The title compound was obtained in the same way that in the Example of the Synthesis the. ^ -NMR (DMSO-de) d (ppm): 6.68 (1H, d, J = 7.3 Hz), 6.89 (1H, dd, J = 7.9, 7.7 Hz), 7 , 25 (1H, d, J = 8.1 Hz), 7.69-7.74 (2H, m), 8.21 (1H, d, J = 2.9 Hz), 8.30 (1H, dd, J = 8.2, 1.3 Hz), 8. 35 (1H, dd, J = 7.4, 1.4 Hz), 8.54 (1H, dd, J = 8.3, 1.7 Hz), 9.15 (1H, dd, J = 4, 3, 1.7 Hz), 10.04 (1H, s ansho), 12.14 (1H, s ansho) Synthesis Example 40a 5-Chloro-N- (3-sia-lH-indol-7-yl) -2-thiophenesulfonamide The title compound was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-de) d (ppm): 6.88 (1H, ddd, J = 7.7, 2.2, 0.73 Hz), 7.16 (1H, dd, J = 7.9 , 7.7 Hz), 7.20 (1H, d, J = 4.0 Hz), 7. 36 (1H, d, J = 4.2 Hz), 7.51 (1H, d, J = 8.1 Hz), 8.23 (1H, d, J = 3.1 Hz), 10.42 ( 1H, s ansho), 12.01 (1H, s ansho) Synthesis Example 41a N- (3-Chloro-lH-indol-7-yl) -4- (methoxysarbonylamino) bensenosulfonamide 170 mg (1.8 mmol ) of methyl chloroformate to a pyridine solution (1 ml) containing 38 mg (0.18 mmol) of the composition of Synthesis Example 3a, followed by agitation at room temperature during noshe. The reassignment mixture was filtered and the residue was purified by ^ "JA ^^ A, ^^^^ chromatography in silica gel solder, to give 20 mg of the title substance. ^ -NMR (DMSO-de) d (ppm): 3.65 (3H, s), 6.80 (1H, d, J = 7.7 Hz), 6.93 (1H, t, J = 7, 9 Hz), 7.21 (1H, dd, J = 7.7, 0.37 Hz), 7.45 (1H, d, J = 2.7 Hz), 7.51 (2H, d, J = 9.0 Hz), 7.63 (2H, d, J = 8.8 Hz), 9.85 (1H, s ansho), 10.07 (1H, s), 10.97 (1H, s ansho) Synthesis Example 42a 4-Asethyl-N- (3-sia-lH-indol-7-yl) bensenosulfonamide The title was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-de) d (ppm): 2.60 (3H, s), 6.74 (1H, d, J = 7.7 Hz), 7.05 (1H, dd, J = 7, 9, 7.7 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.81-7.88 (2H, m), 8.03-8.10 (2H, m), 8.21 (1H, s), 10.18-10.50 (1H, ansha), 11.92-12.07 (1H, m) Synthesis Example 43a N- (3-Chloro-1H-indol-7 -yl) -4- (N-methoxysulfamoyl) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. XH-NMR (DMSO-de) d (ppm): 3.65 (3H, s), 6.73 (1H, d, J = 7.6 Hz), 6.96 (1H, dd, J = 8, 0, 7.6 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 2.4 Hz), 7.98 (4H, s), 10 , 29 (1H, s ansho), 10.76 (1H, s ansho), 11,12 (1H, s ansho) Synthesis Example 44a N- (3-Cyano-lH-indol-7-yl) -β- Strenesulfonamide The title was obtained in the same manner as in Synthesis Example la. ^ -NMR (DMSO-de) d (ppm): 7.14-7.20 (2H, m), 7.32 (2H, s), 7.35-7.47 (4H, m), 7, 60-7.68 (2H, m), 8.23 (1H, s), 9.70-10.03 (1H, ansha), 11.85-12.12 (1H, ansha) Synthesis Example 45a 3 -Cloro-N- (3-sia-lH-indol-7-yl) -2-methylbensenosulfonamide The title was obtained in the same manner as in Synthesis Example la.
XH-NMR (DMSO-de) d (ppm): 2.61 (3H, s), 6.69 (1H, d, J = 7.7 Hz), 7.04 (1H, t, J = 7, 9 Hz), 7.36 (1H, dd, J = 8.1, 7.9 Hz), 7.42 (1H, d, J = 7.9 Hz), 7.73 (1H, dd, J = 8.1, 1.1 Hz), 7.77 (1H, dd, J = 8.0, 0.82 Hz), 8.25 (1H, d, J = 3.1 Hz), 10.37 ( 1H, s), 11.99 (1H, s ansho) Synthesis Example 46a N- (3-Chloro-lH-indol-7-yl) -6-isopropylamino-3-pyridinesulfonamide 400 mg (1, 17 mmol) of the suspension of Synthesis Example 14a and 0.80 ml (9.39 mmol) of isopropylamine to 5 ml of dioxane, followed by scaling at 100 ° C for 7.5 hours in a serrated tube. After concentration, the mixture was dissolved in ethyl acetate, which was then washed successively with dilute ashyrous solution of acidic sulphite, a saturated aqueous solution of sodium bisarbonate and water. The mixture was sessed over magnesium sulfate, and then sonsented. The residue was purified by thin-layer chromatography on silica gel to give 235 mg of the title substance. Melting point: it starts to be quenched from a temperature close to 210 ° C and decomposes from 213 to 215 ° C (recrystallized from ethyl acetate / n-hexane). XH-NMR (DMSO-de) d (ppm): 1.09 (6H, d, J = 6.6 Hz), 3.90-4.08 (1H, m), 6.39 (1H, d, J = 9.0 Hz), 6.90-7.05 (2H, m), 7.24 (1H, d, J = 7.9 Hz), 7.33 (1H, d, J = 7.7 Hz), 7.48 (1H, d, J * 2.4 Hz), 7.54 (1H, dd, J = 9, 0, 2.6 Hz), 8.22 (1H, d, J = 2.6 Hz), 9.65-9.84 (1H, ansha), 10.88-11.04 (1H, m) Synthesis Example 47a N- (3-Chloro-lH-indol-7-yl) -6- [[2- (dimethylamino) ethyl] amino] -3-pyridinesulfonamide The title compound was obtained from the composition of Example Synthesis 14a and N, N-dimethylethylenediamine in the same manner as in Synthesis Example 46a. XH-NMR (DMSO-de) d (ppm): 2.14 (6H, s), 2.35 (2H, t, J = 6.6 Hz), 3.24-3.44 (2H, m) , 6.48 (1H, d, J = 9.0 Hz), 6.92 (1H, d, J = 7.7 Hz), 6.99 (1H, dd, J = 7.9, 7.7 Hz), 7.22 (1H, d, J = 7.9 Hz), 7.27-7.39 (1H, m), 7.47 (1H, d, J = 2.4 Hz), 7.54 (1H, dd, J = 9.0, 2 , 6 Hz), 8.21 (1H, d, J = 2.6 Hz), 10, gilí, 03 (1H, m) Synthesis Example 48a N- (3-Cyano-lH-indol-7-yl) -2-furanosulfonamide The title compound was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-d6) d (ppm): 6.62 (1H, ddd, J = 3.7, 1.8, 0.37 Hz), 6.78 (1H, d, J = 7.5) Hz), 7.04 (1H, d, J = 3.5 Hz), 7.12 (1H, t, J = 7.9 Hz), 7.49 (1H, d, J = 8.1 Hz) , 7.99-8.00 (1H, m), 8.23 (1H, d, J = 3.1 Hz), 10.49 (1H, s ansho), 12.04 (1H, s ansho) Example Synthesis 49a N- (3-Chloro-lH-indol-7-yl) -4- [(dimethylaminosulfonyl) amino] bensenosulfonamide The title compound was obtained from the composition of Synthesis Example 3a and dimethylsulphamoyl sulfate thereof so that in the Example of Synthesis the. XH-NMR (DMSO-d6) d (ppm): 2.66 (6H, s), 6.81 (1H, dd, J = 7.7, 0.92 Hz), 6.95 (1H, dd, J = 7.9, 7.7 Hz), 7.20 (2H, d, J = 8.8 Hz), 7.23 (1H, d, J = 8.1 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.64 (2H, d, J = 8.8 Hz), 10.98 (1H, s ansho) Synthesis Example 50a N- (3-Methyl-lH-indole) 7-yl) -4- (Rethylsulfonyl) bensenosulfonamide 580 mg (15.3 mmol) of sodium borohydride and 150 mg of 10% palladium-sarbon were added to a suspension of 2-propanol (25 ml). 300 mg (1.58 mmol) of 3-formyl-7-nitro-1H-indole is added, followed by reflux for 6 hours. After water was adhered to the reassessment system, the satallizer was removed by filtration. The filtrate was extracted are ethyl acetate, and the extra was washed are brine and then blended over magnesium sulfate. The solvent was evaporated, and the residue was dissolved in 5 ml of pyridine. The mixture was resuspended and treated with 170 mg (0.67 mmol) of 4- (methylsulfonyl) bensenosulfonyl slurry from the same mastic.
I would like in Example la, to give 149 mg of the title substance. ^ -NMR (DMSO-de) d (ppm): 2.18 (3H, s), 3.24 (3H, s), 6.69 (1H, d, J = 7.7 Hz), 6.81 (1H, t, J = 7.7 Hz), 7.06 (1H, S an-sho), 7.25 (1H, d, J = 7.8 Hz), 7.95 (2H, d, J = 8.8 Hz), 8.04 (2H, d, J = 8.2 Hz), 10.14 (1H, s ansho), 10.40 (1H, s ansho) Synthesis Example 51a 3-Cyano-N- (3-sia-lH-indol-7-yl) -bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Example la. ^ -NMR (DMSO-de) d (ppm): 6.71 (1H, d, J = 7.2 Hz), 7.09 (1H, dd, J = 8.0, 7.6 Hz), 7 , 49 (1H, d, J = 8.0 Hz), 7.74 (1H, dd, J = 8.0, 7.6 Hz), 7.94 (1H, d, J = 8.0 Hz) , 8.11-8.14 (2H, m), 8.23 (1H, d, J = 2.8 Hz), 10.30 (1H, s ansho), 12.05 (1H, s ansho) Example Synthesis 52a N- (3-Chloro-lH-indol-7-yl) -4- (N-methyl-methanesulfonamide) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. Melting point: 199 to 201 ° C (desomposition) (resrystallized from ethanol-n-hexane) XH-NMR (DMSO-dβ) d (ppm): 2.98 (3H, s), 3.24 (3H, s) ), 6.83 (1H, dd, J = 7.7, 0.37 Hz), 6.96 (1H, dd, J = 7.9, 7.7 Hz), 7.26 (1H, dd, J = 7.9, 0.55 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.50-7.54 (2H, m), 7.72-7.76 (2H , m), 10.04 (1H, s ansho), 11.02 (1H, s ansho) Synthesis Example 53a N- (3-Chloro-lH-indol-7-yl) -4- [(methanesulfonamide) methyl ] bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. Melting point: begins to be solved from a temperature close to 180 ° C and decomposes from 189 to 191 ° C (recrystallized from ethanol-n-hexane) XH-NMR (DMSO-d6) d (ppm): 2.81 (3H, s), 4.19 (2H, d, J = 6.0 Hz), 6.79 (1H, d, J = 7.7 Hz), 6.94 (1H, dd, J = 7, 9, 7.7 Hz), 7.24 (1H, d, J = 7.9 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.47-7.49 (1H, m), 7.64 (1H, t, J = 6.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 10.00 (1H, s), 11.03 (1H, s ansho) Synthesis Example 54a N- (3-Chloro-lH-indol-7-yl) -4- (1-pyrrolidinyl sulfonyl) bensenosulfonamide The title compound was obtained from 4- (1-pyrrolidinyl sulfonyl) bensenosulfonyl sluride and the set of Produssion Example 10a in the same manner as in the Synthesis Example. ^ -NMR (DMSO-de) d (ppm): 1.55-1.59 (4H, m), 3.07-3.11 (4H, m), 6.71 (1H, d, J = 7 , 6 Hz), 6.95 (1H, ddd, J = 8.2, 7.4, 1.2 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.46 (1H, d, J = 2.4 Hz), 7.89 (2H, d, J = 8.8 Hz), 7.92 (2H, d, J = 8.4 Hz), 10.18 (1H, s an-sho), 11.03 (1H, s ansho) Synthesis Example 55a N- (3-Cyano-lH-indol-7-yl) -l-met? L-4-imidazolesulfonamide The title compound was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-de) d (ppm): 3.61 (3H, s), 7.00 (1H, dd, J = 7.7, 0.92 Hz), 7.07 (1H, dd, J = 7.9, 7.7 Hz), 7.35 (1H, d, J = 7.9 Hz), 7.75-7.76 (2H, m), 8.19 (lH, d, J = 3.1 Hz), 10.03 (1H, s ansho), 11.92 (1H, s ansho) Synthesis Example 56a N- (3-Chloro-lH-indol-7-yl) -6- [( 2-hydroxyethyl) amino] -3-pyridinesulfonamide The title compound was obtained from the composition of Synthesis Example 14a and 2-aminoethanol in the same manner as in Synthesis Example 46a. ^ -RN (DMSO-de) d (ppm): 3.24-3.40 (2H, m), 3.42-3.52 (2H, m), 4.66-4.77 (1H, m ), 6.48 (1H, d, J = 9.3 Hz), 6.92 (1H, d, J = 7.7 Hz), 7.00 (1H, t, J = 7.7 Hz), 7.24 (1H, d, J = 7.7 Hz), 7.40-7.62 (2H, m), 7.48 (1H, d, J = 2.2 Hz), 8.22 (1H , d, J »2.6 Hz), 9.63-9.90 (1H, ansha), 10.90-11.07 (1H, m) Synthesis Example 57a N- (3-Chloro-lH- ndoI -7-yl) -6-mercapto-3-pyridinesulfonamide 340 mg (0.99 mmol) of the somatum of Synthesis Example 14a and 151 mg (1.98 mmol) of thiourea were added to 5 ml of ethanol, followed by salting out at reflux for 2 hours. After sonication, 1.6 ml of water and 57 mg of sodium sarbonate were added to the residue and the resulting mixture was stirred at room temperature for 10 minutes. 85 mg of sodium hydroxide were added and the mixture was stirred for 10 additional minutes, followed by elimination of the insoluble products by filtration. The filtrate was assiduously acidic, and the resulting precipitate was filtered off, washed, water, then dissolved in tetrahydrofuran and blended on magnesium sulfate. After stripping, the residue was purified by chromatography in a thin layer of silica gel to give 121 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 6.84 (1H, d, J = 7.6 Hz), 7.03 (1H, t, J = 7.6 Hz), 7.28 (1H , d, J = 9.2 Hz), 7.31 (1H, d, J = 7.6 Hz), 7.44 (1H, dd, J = 9.2, 2.4 Hz), 7.48 (1H, d, J = 2.6 Hz), 7.68 (1H, d, J = 2.4 Hz), 9.58-9.80 (1H, ansha), 11.08-11.19 ( 1H, m) Synthesis Example 58a Asid 7- (4-slorobensenosulfonamide) -lH-indole-2-sarboxylyl The title compound was obtained in the same manner as in Synthesis Example la. XH-NMR (DMSO-de) d (ppm): 6.65 (1H, d, J = 7.6 Hz), 6.87 (1H, dd, J = 8.0, 7.6 Hz), 7 , 00 (1H, s), 7.26 (1H, d, J = 8.0 Hz), 7.56-7.65 (2H, m), 7.68-7.77 (2H, m), 9.62-10.00 (1H, ansha), 11.40-11.74 (1H, ansha) Synthesis Example 59a N- (3-Chloro-lH-indol-7-yl) -6-cyclo-propylamino -3-pyridine sulfonamide The title compound was obtained in the same manner as in Synthesis Example 46a. Melting point: melting at a temperature close to 228 ° C and dessomposing from 233.5 to 235 ° C (recrystallized from ethyl acetate-n-hexane) XH-NMR (DMSO-de) d (ppm): 0, 36-0.46 (2H, m), 0.63-0.75 (2H, m), 2.44-2.64 (1H, m), 6.45-6.64 (1H, m), 6.93 (1H, d, J = 7.7 Hz), 7.00 (1H, dd, J = 7.9, 7.7 Hz), 7.24 (1H, d, J = 7.9 Hz ), 7.49 (1H, d, J = 2.7 Hz), 7.57-7.73 (2H, m), 8.25 (1H, d, J = 2.6 Hz), 9.68 -9.90 (1H, ansha), 10.92-11.04 (1H, m) Synthesis Example 60a N- (3-Cyano-lH-indol-7-yl) -5-methyl-3-pyridinesulfonamide obtained the title of the title in the same way as in the Example of the Synthesis. Melting point: gradually decomposes at a temperature close to 288 ° C (recrystallized from ethanol-n-hexane) 4.-NMR (DMSO-de) d (ppm): 2.33 (3H, s), 6.75 ( 1H, d, J = 7.7 Hz), 7.09 (1H, dd, J = 7.9, 7.7 Hz), 7.48 (1H, d, J = 7.9 Hz), 7, 87-7.91 (1H, m), 8.22 (1H, d, J = 3.1 Hz), 8.58-8.67 (2H, m), 10.28 (1H, s ansho), 11.95-12.08 (1H, m) Synthesis Example 61a N- (3-Chloro-lH-indol-7-yl) -4- (N-methylsulfamoyl) bensenosulfonamide The title compound was obtained in the same manner that in the Synthesis Examples la and 2a. Hi-NMR (DMSO-de) d (ppm): 2, 39 (3H, d, J = 5.2 Hz), 6.71 (1H, dd, J = 7.8, 2.0 Hz), 6.96 (1H, dd, J = 8.0, 7 , 6 Hz), 7.30 (1H, d, J = 8.0 Hz), 7.48 (1H, d, J = 2.8 Hz), 7.68 (1H, s, J = 4.9 Hz), 7.87-7.93 (4H, m), 10.20 (1H, s ansho), 11.08 (1H, s ansho) Synthesis Example 62a N- (3-Chloro-1H-indole) 7-yl) -4- [2- (methanesulfonamide) ethyl] bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. H-NMR (DMSO-de) d (ppm): 2.73-2.81 (5H, m), 3.13-3.19 (2H, m), 6.82 (1H, d, J = 7 , 7 Hz), 6.95 (1H, dd, J = 8.1, 7.7 Hz), 7.09 (1H, t, J = 5.9 Hz), 7.24 (1H, d, J = 8.1 Hz), 7.39 (2H, d, J = 8.2 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.68 (2H, d, J = 8 ,4 lü "to ** M ^ -J" M-wa1. T a TÍÍMÉ.
Hz), 9.97 (1H, s ansho), 11.02 (1H, s ansho) Synthesis Example 63a N- (3-Chloro-lH-indol-7-yl) -4- (sulfamoylmethyl) bensenosulfonamide Reagent 389 mg (1.44 mmol) of the compound of Produssion Example 6a are 159 mg (1.2 mmol) of the compound of Produssion Example 2a and the substitution prodrug was treated in the same manner as in Example 1, give 233 mg of N- (lH-indol-7-yl) -4- (sulfamoylmethyl) bensenosulfonamide. The compound was chlorinated in the same manner as in Example 2a, to give 160 mg of the title compound. Melting point: 237 to 238, 5 ° C (decomposition) (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 4.33 (2H, s), 6.84 (1H , dd, J = 7.7, 0.73 Hz), 6.93 (2H, s), 6.92-6.97 (1H, m), 7.24 (1H, dd, J = 7.9 , 0.37 Hz), 7.48 (1H, d, J = 2.7 Hz), 7.48-7.52 (2H, m), 7.75-7.79 (2H, m), 10 , 08 (1H, s ansho), 11.04 (1H, s ansho) Synthesis Example 64a N- (3-Chloro-lH-indol-7-yl) -4-thiocarbamoylbensenosulfonamide 400 mg (1.21 mmol ) of the suspension of Synthesis Example 10a in 10 ml of dimethylformamide, to which 0.5 ml of triethylamine was then added. Hydrogen sulfide was passed through the mixture at a bath temperature of 60 to 70 ° C for 45 minutes. After stripping, the residue was dissolved in ethyl acetate, washed thoroughly with dilute slurry, a saturated aqueous solution of sodium bicarbonate and water, and blended with magnesium sulfate. After evaporating the solvent, the residue was purified by chromatography on silica gel solvate to give 355 mg of the title suspension. Melting point: 223 to 225 ° C (desomposition) (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.81 (1H, d, J = 7.7 Hz), 6.96 (1H, dd, J = 7.9, 7.7 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.50 (1H, d, J = JB t-, l.AA. < , j ....--. > '' 'TMm.llftli.lÉMl.iii 2,7 Hz), 7,73-7,80 (2H, m), 7,86-7,93 (2H, m), 9,58-9,73 (lH, m ansho), 10.02-10.18 (lH, m ansho), 10.15 (1H, s), 11.03-11.12 (1H, m) Synthesis Example 65a 5-Bromo- N- (3-sia-lH-indol-7-yl) -2-pyridinesulfonamide The title compound was obtained in the same manner as in Synthesis Example la. Melting point: 245.5 to 246, 5 ° C (desomposition) (recrystallized from ethyl acetate / n-hexane) XH-NMR (DMSO-de) d (ppm): 6.82 (1H, d, J = 7.7 Hz), 7.07 (1H, dd, J = 7.9, 7.7 Hz), 7.44 (1H, d, J = 7.9 Hz), 7.80 (1H, d, J- 8.2 Hz), 8.23 (1H, d, J = 2.2 Hz), 8.29 (1H, dd, J = 8.2, 2.2 Hz), 8.92 (1H, d, J = 2.2 Hz), 10.42-10.67 (1H, ansha), 11.93-12.08 (1H, m) Synthesis Example 66a N- (3-Cyano-lH-indol-7-yl) -2-naphthalenesulfonamide The title compound was obtained in the same manner as in Synthesis Example la. ^ -NMR (DMSO-de) d (ppm): 6.74 (1H, dd, J = 7.6, 2.8 Hz), 7.00 (1H, dd, J = 7.9, 7.7 Hz), 7.39 (1H, dd, J = 8.0, 0.46 Hz), 7.61-7.72 (2H, m), 7.80 (1H, dd, J = 8.6, 1.8 Hz), 8.01 (1H, d, J = 8.1 Hz), 8 , 08 (1H, s), 8.10 (1H, s), 8.21 (1H, d, J = 2.9 Hz), 8.34 (1H, d, J = 1.6 Hz), 10.23 (1H, s ansho), 12.01 (1H, s ansho) Synthesis Example 67a N- (3-Asethyl-lH-indol-7-yl) -3-sloro-bensenosulfonamide The title was obtained in the same manner as in Synthesis Example la. H-NMR (DMSO-de) d (ppm): 2.44 (3H, s), 6.65 (1H, d, J = 7.5 Hz), 7.01 (1H, dd, J = 7, 9, 7.7 Hz), 7.53-7.63 (2H, m), 7.69-7.73 (2H, m), 8.01 (1H, dd, J = 8.1, 0, 73 Hz), 8.26 (1H, d, J * 2.9 Hz), 10.10 (1H, s), 11.75 (1H, s ansho) Synthesis Example 68a 4-Amino-N- (5-bromo-3-sia-lH-indol-7-yl) ) bensenosulfonamide The title compound was obtained by hydrogension of N- (5-bromo-3-sia-lH-indol-7-yl) -4-nitrobensenosulfonamide, obtained from 4-nitrobensenosulfonyl sluride and the composition of Example Production 14a in the same manner as in Example la, at normal temperature under normal pressure in the presence of platinum oxide. XH-NMR (DMSO-de) d (ppm): 6.07 (2H, broad s), 6.52 (2H, d, J = 8.4 Hz), 6.97-6, 99 (1H, m), 7.36 (2H, dd, J = 8.7, 1.6 Hz), 7.51 (1H, broad s), 8.25 (1H, s), 9.93 (1H, d, J = 5.5 Hz), 11.97 (1H, s ansho) Synthesis Example 69a N- (3-Chloro-lH-indol-7-yl) -4- (N-ethylsulfamoyl) bensenosulfonamide The title was obtained in the same manner as in Synthesis Examples la and 2a. Melting point: 213.5 to 215 ° C (recrystallized from ethanol / n-hexane) ^ -RMN (DMSO-de) d (ppm): 0.90 (3H, t, J = 7.2 Hz), 2 , 76 (2H, ds, Jd = 5.8 Hz, Js = 7.2 Hz), 6.70 (1H, d, J = 7.4 Hz), 6.95 (1H, dd, J = 8, 0, 7.6 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 2.8 Hz), 7.78 (1H, t, J = 5.6 Hz), 7.90 (4H, s), 10.18 (1H, s ansho), 11.06 (1H, s ansho) Synthesis Example 70a N- (3-Chloro-lH-mdol-7 -? l) -4- (ethanesulfonamide) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Example 4a. Melting point: 214 to 215 ° C (desomposition) (recrystallized from ethanol / n-hexane) H-NMR (DMSO-de) d (ppm): 1.14 (3H, t, J = 7.3 Hz), 3.16 (2H, s, J = 7.3 Hz), 6.82 (1H, d, J = 7.5 Hz), 6.96 (1H, dd, J = 7.9, 7.7 Hz) ), 7.23 (2H, d, J = 8.8 Hz), 7.24 (1H, d, J = 7.5 Hz), 7.47 (1H, d, J = 2.6 Hz), 7.66 (2H, d, J = 8.8 Hz), 9.90 (1H, S ansho), 10.37 (1H, s ansho), 10.96 (1H, s ansho) Synthesis Example 71a N - (3-Chloro-lH-indol-7-yl) -6- [(2-siamethyl) ammo] -3-pyridinesulfonamide The title was obtained in the same manner as in Synthesis Example 46a. XH-NMR (DMSO-de) d (ppm): 2.72 (2H, t, J = 6.4 Hz), 3.46-3.55 (2H, m), 6.53 (1H, d, J = 9.0 Hz), 6.90 (1H, d, J = 7.7 Hz), 6.99 (1H, dd, J = 7.9, 7.7 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.48 (1H, d, J = 2.6 Hz), 7.61 (1H, dd, J = 9.0, 2.4 Hz), 7.78- 7.87 (1H, m), 8.25 (1H, d, J = 2.4 Hz), 9.70-9.95 (1H, ansha), 10.92-11.04 (1H, m) Synthesis Example 72a N- (3-Chloro-lH-indol-7-yl) -4- (N-methylsarbamoyl) bensenosulfonamide 533 mg (1.68 mmol) of the somatic compound of Synthesis Example 9a was dissolved in a mixed solution of 5 ml of dimethylformamide and 2.5 ml of dimethyl sulfoxide, to which 171 mg (2.53 mmol) of methylamine hydrosulphide and 705 μl (5.06 mmol) of triethylamine were added. 436 μl (2.02 mmol) of diphenylphosphorylazide were added, followed by agitation at room temperature during noshe. Then, the mixture was filtered and extracted with ethyl acetate. The extra washes are dilute slurry, diluted, saturated asbestos dissolution of sodium bisarbonate and water, and brazed on magnesium sulfate. After stripping, the residue was purified by silica gel solvate chromatography, to give 465 mg of N- (lH-indol-7-yl) -4- (N-ethylsarbamoyl) bensenosulfonamide. The obtained composition was slit in the same manner as in Synthesis Example 2a, to give 413 mg of the title substance. Melting point: 252 to 253 ° C (desomposition) (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 2.76 (3H, d, J = 4.6 Hz), 6.74 (1H, d, J = 7.7 Hz), 6.94 (1H, dd, J = 7.9, 7.7 Hz), 7.27 (1H, d, J = 7.9 Hz ), 7.49 (1H, d, J = 2.7 Hz), 7.76-7.83 (2H, m), 7.87-7.94 (2H, m), 8.61 (1H, s, J = 4.6 Hz), 10.10 (1H, s), 11.03-11.13 (1H, m) Synthesis Example 73a N- (3-sloro-lH-indol-7-il) -4- (Methylsulfonylmethyl) bensenosulfonamide 510 mg of the somatum of Synthesis Example 34a was oxidized using 30% ropy hydrogen peroxide in the same manner as in Example 23a, to give 307 mg of the title compound. Melting point: melting at a temperature close to 225 ° C and gradually disentangling at a temperature close to 235 ° C (recrystallized from ethanol / n-hexane) (^? - NMR (DMSO-de) d (ppm): 2.88 (3H, s), 4.57 (2H, s), 6.77 (1H, d, J = 7.6 Hz), 6.94 (1H, dd, J = 7.9, 7, 7 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.51-7.56 (2H, m), 7 , 73-7.78 (2H, m), 10.05 (1H, s ansho), 11.04 (1H, broad s) Synthesis Example 74a N- (3-Chloro-lH-indol-7-yl) -4- (N, N ~ dimethylsulfamoyl) bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a.XH-NMR (DMSO-de) d (ppm): 2.57 (6H, s), 6.71 (1H, dd, J = 7.4, 0.6 Hz), 6.97 (1H, dd, J = 8.0, 7.6 Hz), 7.31 (1H, d , J = 8.0 Hz), 7.47 (1H, d, J = 2.8 Hz), 7.86 (2H, d, J = 8.4 Hz), 7.91 (2H, d, J = 8.4 Hz), 10.19 (1H, s ansho), 11.04 (1H, s ansho) Synthesis Example 75a N- (3-Chloro-lH-indol-7-yl) -4- (1 -pyrrolidinyl-aryl-phenyl) bensenosulfonamide. the title in the same way as in the Synthesis Example la. XH-NMR (DMSO-d6) d (ppm): 1.79 (2H, dt, Jd = 12.8 Hz, Jt = 6.4 Hz), 1.85 (2H, dt, Jd = 13.6 Hz , Jt = 6.8 Hz), 3.22 (2H, t, J = 6.4 Hz), 3.44 (2H, t, J = 6.8 Hz), 6.78 (1H, d, J = 7.2 Hz), 6.96 (1H, dd, J = 8.0, 7.2 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.47 (1H, d , J = 2.4 Hz), 7.60 (2H, d, J = 8.0 Hz), 7.74 (2H, d, J = 8.4 Hz), 10.06 (1H, s ansho) , 11.01 (1H, s ansho) Synthesis Example 76a 3-Chloro-N- (3-sloro-lH-indol-7-yl) -N-methyl-bensenosulfonamide 120 mg (0.352 mmol) was dissolved from the composition of Example Synthesis 7a in 10 ml of dimethylformamide, to which -JG then 19.2 mg (0.479 mmol) of sodium hydride (60%) were added. After stirring at room temperature for 30 minutes, 30 μl (0.482 mmol) of methyl iodide was added. After two hours, water is admissed, followed by extrassion are ethyl acetate. The sapa organelle was washed in water and dried over magnesium sulfate. After showing, the residue was purified by chromatography in a thin layer of silica gel, to give 87 mg of the title substance. XH-NMR (DMSO-de) d (ppm): 3.26 (3H, s), 6.51 (1H, dd, J = 7.6, 0.64 Hz), 7.00 (1H, dd, J = 7.9, 7.7 Hz), 7.47 (1H, d, J = 8.1 Hz), 7.53 (1H, d, J = 2.7 Hz), 7.54-7, 59 (2H, m), 7.65 (1H, t, J = 7.9 Hz), 7.84 (1H, ddd, J = 8.1, 2.1, 1.1 Hz), 11.62 (1H, S ansho) Synthesis Example 77a N- (3, 4-Dichloro-lH-indol-7-yl) -4- (sulfamoylmethyl) bensenosulfonamide The title was obtained in the same manner as in the Synthesis Example the. Melting point: gradual deposition from a temperature close to 297 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 4.34 (2H, s), 6.72 (1H, d, J = 8.1 Hz), 6.93 (2H, s), 6.94 (1H, d, J = 8.1 Hz), 7.51 (2H, d, J = 8, 1 Hz), 7.57 (1H, dd, J = 2.7, 0.55 Hz), 7.75 (2H, d, J = 8.2 Hz), 10.10 (1H, s ansho), 11.44 (1H, s ansho) Synthesis Example 78a N- (3-Cyano-lH-indol-7-yl) -4- [2- (methylsulfonyl) ethyl] bensenosulfonamide The title compound was obtained in the same manner that in the Example of Synthesis the. Hl-R N (DMSO-de) d (ppm): 2.94 (3H, s), 3.03-3.08 (2H, m), 3.42-3.47 (2H, m), 6 , 77 (1H, dd, J = 7.7, 0.37 Hz), 7.05 (1H, t, J = 7.9 Hz), 7.41 (1H, d, J = 8.1 Hz) , 7.46 (2H, d, J = 8.2 Hz), 7.66 (2H, d, J = 8.2 Hz), 8.20 (1H, s), 10.09 (1H, s ansho) ), 11.92 (1H, s ansho) Synthesis Example 79a N- (3-Chloro-lH-indol-7-yl) -4- (N-methylasetamido) bensenosulfonamide The title substance was obtained in the same manner as in the Synthesis Examples la and 2a. H-NMR (DMSO-de) d (ppm): 1.84 (3H, s ansho), 3.16 (3H, s), 6.81 (1H, d, J = 7.7 Hz), 6, 96 (1H, dd, J = 8.0, 7.6 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.45-7.49 (2H, m), 7.47. (1H, d, J = 2.7 Hz), 7.70-7.75 (2H, m), 10.02 (1H, s ansho), 11.01 (1H, s ansho) Synthesis Example 80a N - (3-Chloro-lH-indol-7-yl) -6-hydroxy-3-pyridinesulfonamide They were added dropwise, under cooling, under ice, to a solution of the suspension of Example 33a (100 mg, 0.31 mmol) dissolved in 2 ml of a rough glasial acetic acid, 1 ml of an asuous dissolution containing 32 mg (0.46 mmol) of sodium nitrite. After stirring for one hour, the mixture was adjusted to approximately pH 8 by adduction of an asuous dissolution of sodium bisarbonate and further stirred for 10 minutes. The reassuring mixture was extracted with ethyl acetate, and the extra was washed with water, blended on magnesium sulfate and filtered. Then, the residue was puri fi ed by a thin sample of silica gel to give 54 mg of the title substance. Melting point: 244-245 ° C (desomposition) (recrystallized from ethyl acetate / n-hexane) XH-NMR (DMSO-d6) d (ppm): 6.39 (1H, d, J = 9.5 Hz ), 6.88 (1H, d, J = 7.7 Hz), 7.04 (1H, dd, J = 7.9, 7.7 Hz), 7.32 (1H, d, J = 7, 9 Hz), 7.50 (1H, d, J = 2.7 Hz), 7.58 (1H, dd, J = 9.5, 3.1 Hz), 7.64 (1H, d, J = 3.1 Hz), 9.76-9.94 (1H, ansha), 11.01-11.13 (1H, m), 11.98-12.15 (1H, ansha) Synthesis Example 81a N- (3-Chloro-lH-indoI-7-yl) -4- [2- (N-methylmethanesulfonamido) tyl] bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. XH-NMR (DMS0-d6) d (ppm): 2.69 (3H, s), 2.76 (3H, s), 2.86 (2H, t, J = 7.5 Hz), 3.26 (2H, t, J = 7.5 Hz), 6.78 (1H, dd, J = 7.4, 0.55 Hz), 6.94 (1H, t, J = 7.7 Hz), 7.24 (1H, dd, J * 7.7, 0.37 Hz), 7.39 ( 2H, d, J = 8.2 Hz), 7.48 (1H, d, J = 2.6 Hz), 7.66 (2H, d, J = 8.2 Hz), 9.94 (1H, s ansho), 11.02 (1H, S ansho) Synthesis Example 82a N- (3-Chloro-lH-indol-7-yl) -4- (trifluoromethanesulfonamido) bensenosulfonamide 128 μl (0.76 mmol) was added. anhydride of the acid trifluoromethanesulfoniso to a pyridine solution (5 ml) containing 62 mg (0.19 mmol) of the composition of Synthesis Example 3a at 0 ° C, followed by agitation as it was during noshe. The dissolution of reassurance evaporated. A dissolution of acid phosphate buffer having a pH of 7 was adhered to, followed by extrasysis are ethyl acetate. Then, the extra was washed is brine and brazed on magnesium sulfate. The solvent was evaporated and the residue was purified by chromatography in silica gel solnum, to give 20 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 6.79 (1H, d, J = 7.7 Hz), 6.94 (1H, dd, J = 7.9, 7.7 Hz), 7 , 16 (2H, d, J = 8.6 Hz), 7.23 (1H, d, Js 7.9 Hz), 7.46 (1H, d, J = 2.7 Hz), 7.58 ( 2H, d, J = 8.1 Hz), 9.84 (1H, s ansho), 10.98 (1H, s ansho) Synthesis Example 83a N- (3-Chloro-lH-indol-7-yl) -4- [(N-methylmethanesulfonamido) methyl] bensenosulfonamide The title compound was obtained in the same manner as in Synthesis Examples la and 2a. Melting point: 200.5 to 202 ° C (recrystallized from ethanol) XH-NMR (DMSO-de) d (ppm): 2.63 (3H, s), 2.94 (3H, s), 4.27 (2H, s), 6.80 (1H, d, J = 7.3 Hz), 6.95 (1H, dd, J = 8.1, 7.5 Hz), 7.25 (1H, d, J = 7.9 Hz), 7.45 (2H, d, J = 8.2 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.74 (2H, d, J = 8.2 Hz), 10.00 (1H, s), 11.00 (1H, s ansho) Synthesis Example 84a 3-Chloro-N- (3-sloro-lH-pyrrolo [2, 3-s] pyridine -7-yl) bensenosulfonamide. To 600 ml of ashy ammonia, 600 mg (3.05 mmol) of 7-bromo-lH-pyrrolo [2, 3-c] pyridine synthesized from 2-bromo-3-nitropyridine were added to 84 ml. in the same way as in the Example of Production, 194 mg of powdered sachet and 603 mg of superoxide slurry. The mixture was heated in a serrated tube at 120 ° C for 15 hours and then treated, to give 170 mg of 7-amino-1H-pyrrolo [2, 3-s] pyridine. The resulting prodrug was reacted and treated in the same manner as in Examples la and 2a, to give 57 mg of the title substance. ^ -NMR (DMSO-de) d (ppm): 6.93 (1H, d, J = 6.6 Hz), 7.45 (1H, dd, J = 6.6, 5.8 Hz), 7 , 53 (1H, dd, J = 8.0, 7.6 Hz), 7.61 (1H, d, J = 7.6 Hz), 7.73 (1H, d, J = 2.8 Hz) , 7.85 (1H, d, J = 8.0 Hz), 7.96 (1H, d, J = 1.2 Hz), 11.90-12.10 (1H, m), 12.72 ( 1H, s ansho) Synthesis Example 85a N- (3-Chloro-lH-indol-7-yl) -4- [3- (1-ylidazolyl) propyl] bensenosulfonamide Were adhered to 4- (3-bromopropyl) -N - (3-sloro-lH-indol-7-yl) bensenosulfonamide (213 mg, 0.5 mmol) 170 mg (2.5 mmol) of imidazole and 6 ml of dimethylformamide, followed by scaling at 80 ° C. 3 hours under nitrogen atmosphere. Then, the reassuring mixture was poured into water and extracted is sloroform. The extra was blended on magnesium sulfate and concentrated. Then, the residue was purified by silica gel column chromatography, to give 160 mg of the title base. Melting point: 86 to 90 ° C XH-NMR (DMSO-de) d (ppm): 1.95-2.04 (2H, m), 2.55 (2H, t, J = 7.9 Hz) , 3.92 (2H, t, J = 7.1 Hz), 6.81 (1H, dd, J = 7.7, 0.9 Hz), 6.88 (1H, t, J = 1.1 Hz), 6.94 (1H, dd, J = 7.9, 7.7 Hz), 7.16 (1H, t, J = 1.2 Hz), 7.23 (1H, d, J = 7 , 7 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.47 (1H, d, J = 2.7 Hz), 7.60 (1H, s ansho), 7.65 (2H, d, J = 8.4 Hz), 9.91-10.01 (1H, m), 10.98-11.02 (1H, m) Synthesis Example 86a N- (3-Chloro-lH -indol-7-yl) -4- [N- [2- (2-pyridinyl) ethyl] sarbamoyl] bensenosulfonamide 2.82 g (12.8 mmol) of 4- (slorosulfonyl) benzoiso y 1 were reacted. 42 g (8.54 mmol) of 7-amino-3-sloro-lH-indole in pyridine at room temperature are stirred during the noshe, to give 2.33 g of asido 4- [N- (3-sloro -lH-indol-7-yl) sulfamoyl] benzoiso. At 303 mg (0, 86 mmol) of the prodrug was subjected to 260 μl of dimethylformamide, 204 μl (0.95 mmol) of diphenylphosphorylazide, 132 μl (0.95 mmol) of triethylamine and 113 μl (0.94 mmol) of 2- (2). -aminoethyl) pyridine, followed by agitation at room temperature during noshe. After screeching, ethyl acetate was added and a saturated saturated dissolution of sodium bisarbonate was added. The sap organelle was separated and washed is brine. After evaporating the solvent, the residue was purified by silica gel column chromatography, to give 175 mg of the title compound. Melting point: 220.5 to 222 ° C XH-NMR (DMSO-de) d (ppm): 2.95-2.99 (2H, m), 3.56-3.62 (2H, m), 6.75 (1H, d, J = 7.5 Hz), 6.94 (1H, dd, J = 7.9, 7.7 Hz), 7.19-7.28 (3H, m), 7 , 48 (1H, d, J = 2.8 Hz), 7.69 (1H, dt, Jd = 1, 8 Hz, Jt = 7.7 Hz), 7.79 (2H, d, J = 8, 6 Hz), 7.88 (2H, d, J = 8.6 Hz), 8.48-8.51 (1H, m), 8.75 (1H, t, J = 5.2 Hz), 10 , 09-10.12 (1H, m), 11.06-11.09 (1H, m) Synthesis Example 87a 4-Amidino-N- (3-sloro-lH-indol-7-yl) bensenosulfonamide Were adhered 3.3 ml (3.3 mmol) of a hexane solution containing 1.0 M trimethylaluminum and 10 ml of toluene at 162 mg (3.0 mmol) of ammonium slurry. After the gas generation was dry, the mixture was evaporated until the sanity of solution was about 3 ml. While stirring, 97 mg (0.30 mmol) of the suspension of Produssion Example 4a was added and the mixture was heated at 80 ° C for 4 hours. After cooling, ammonia was detected, the insoluble products were removed by filtration. tH ^ h-? Wfol ^ A ^ .fcMl ^^ bles and the filtrate was filtered. Ethyl acetate was added, the insoluble products were removed by filtration and the filtrate was consented. The residue was purified by chromatography on silica gel solnum, to give 35 mg of the title base. XH-NMR (DMSO-de) d (ppm): 6.93 (1H, dd, J = 7.7, 1.5 Hz), 6.96 (1H, dd, J = 7.7, 7.5 Hz), 7.24 (1H, dd, J = 7.5, 1.3 Hz), 7.50 (1H, d, J = 2.7 Hz), 7.90 (2H, d, J = 8 , 6 Hz), 8.01 (2H, d, J = 8.6 Hz), 9.16-9.62 (2H, ansha), 10.40-10.75 (1H, broad), 11.50 (1H, s) Synthesis Example 88a N- (3-Chloro-lH-indol-7-yl) -4- [N- [2- (1-imidazolyl) ethyl] sulfamoyl] benzenesulfonamide 557 mg (1, 13 mmol) of 4- [N- (2-bromoethyl) sulfamoyl] -N- (3-sloro-lH-mdol-7-yl) bensenosulfonamide and 820 mg (12.0 mmol) of imidazole to 10 ml of dimethylformamide and the mixture was stirred at 80 ° C for 2 days. After stripping, the residue was dissolved in ethyl acetate. The mixture was washed with water, dried over sodium sulfate and filtered. The residue was purified by chromatography on silica gel solumone to give 324 mg of the title substance. Melting point: it starts to be gradually released from a temperature close to 200 ° C and decomposes from 218 to 221 ° C (recrystallized from ethanol / n-hexane) XH-NMR (DMSO-de) d (ppm): 3, 05 (2H, ddd, J = 6.2, 6.0, 5.9 Hz), 3.96 (2H, dd, J = 6.0, 5.9 Hz), 6.69-6.72 ( 1H, m), 6.84 (1H, s ansho), 6.92 (1H, dd, J = 7.9, 7.7 Hz), 7.08 (1H, s ansho), 7.26 (1H , d, J = 7.5 Hz), 7.44 (1H, d, J = 2.7 Hz), 7.55 (1H, s ansho), 7.82-7.88 (4H, m), 8.06 (1H, t, J = 5.9 Hz), 10.18-10.36 (1H, ansha), 11.09 (1H, d, J = 2.4 Hz) Synthesis Example 89a 3- (5-Bromonisothinamido) -N- (3-sia-1H-indol-7-yl) bensenosulfonamide. Reassess 785 mg (3.54 mmol) of 3-nitrobensenosulfonyl slurry are 506 mg (3.22 mmol) of the compound * »? ? *. ¿*** .... ^^^ m.a .., Mt [, | ? r jy | Figure US07327073-20130101-C00006 is prepared in accordance with Example Produssion 3a in the same manner as in Produssion Example 4a and treated, to give 950 mg of N-. { 3- siane-lH-indol-7-yl) -3-nitrobensenosulfonamide. The prodrug was reduced using powdered / rough slurry-dried forms in 30 ml of methanol according to a conventional method, to give 459 mg of 3-amino-N- (3-sia-lH-indol-7-yl) bensenosulfonamide. 109 mg (0.35 mmol) of the prodrug was dissolved in 2 ml of pyridine and 179 mg (0.70 mmol) of 5-bromonisothinoyl sluride hydrosulphide was added. After stirring at room temperature during noshe, the mixture was filtered. A diluted asymmetrical dissolution of a strong trace was adhered to the residue. The resultant presipitate was resuscitated by filtration, and washed suesively is water, a dilute diluted dissolution of sodium bisarbonate, water and ether. The precipitates were dissolved in tetrahydrofuran, and the mixture was sessed over magnesium sulfate and filtered. Filtering was carried out by filtering the presyred glass by the addition of ether and n-hexane, to give 108 mg of the title substance. XH-NMR (DMSO-de) d (ppm): 6.81 (1H, dd, J = 7.7, 0.7 Hz), 7.07 (1H, t, J = 7.9 Hz), 7 , 42 (1H, dd, J = 7.9, 0.7 Hz), 7.47-7.51 (1H, m), 7.55 (1H, t, J = 7.9 Hz), 7, 93-7.97 (1H, m), 8.21- 8.23 (1H, m), 8.31 (1H, t, J = 1.8 Hz), 8.55 (1H, dd, J = 2.4, 2.0 Hz), 8.93 (1H, d, J = 2.4 Hz), 9.06 (1H, d, J = 2.0 Hz), 10.23-10.25 ( 1H, m), 10.75 (1H, s ansho), 11.94-11.96 (1H, m) Synthesis Example 90a N- (3-Chloro-lH-indol-7-yl) -4- [ N- (2-thiazolyl) sulfamoyl] bensenosulfonamide 5.2 g (20.4 mmol) of sulfatiazole were added to a mixture of 14 ml of water and 3.4 ml of solid sulphuridose solution and the mixture was stirred. A saturated aqueous solution of 2.1 g (30.4 mmol) of sodium nitrite at 0 ° C or less was added dropwise to the mixture. Then, 5 ml of rough acetic acid was added, followed by agitation at 5 ° C for approximately 10 minutes. It was added drop by drop A dissolving in acetic acid is sulfur dioxide (dissolution prepared by saturation of 18 ml of acid acetic acid are sulfur dioxide and then 830 mg of copper slurry-dihydrate were added to the reaction solution at 0 ° C with stirring. After 5 minutes, the reaction solution was poured over ice-water. The precipitates were collected by filtration, washed with water and sessed to give 2.9 g of 4-slorosulfonyl-N- (2-thiazolyl) bensenosulfonamide. 570 mg (1.68 mmol) of the produst were reassumed to 200 mg (1.2 mmol) of the product of Produssion Example in the same manner as in Produssion Example 4a and treated, to give 456 mg of the solution. of the title. XH-NMR (DMSO-de) d (ppm): 6.68 (1H, dd, J = 7.5, 0.73 Hz), 6.87 (1H, d, J = 4.6 Hz), 6 , 93 (1H, dd, J = 8.1, 7.5 Hz), 7.26-7.30 (1H, m), 7.28 (1H, d, J = 4.6 Hz), 7, 46 (1H, d, J = 2.7 Hz), 7.82-7.88 (2H, m), 7.88-7.94 (2H, m), 10.10-10.26 (1H, ansha), 11.04-11.10 (1H, m), 12.83-13.01 (1H, ansha) Synthesis Example 91a 5-Chloro-N- (3-sloro-lH-indol-7-il ) -4- (5-Methyl-3-pyridinesulfonamido) -2-thiophenesulfonamide Reaction 645 mg (2.46 mmol) of 5-sloro-4-nitro-2-thiophenesulfonyl slurry are 410 mg (2.46 mmol) ) of the example of Produssión Example in the same way qu. in Produssion Example 4a and treated, to give 194 mg of 5-sloro-N- (3-sloro-lH-indol-7-yl) -4-nitro-2-thiophenesulfonamide. The prodrug was reduced using polyev / rough slurry ssensen in 10 ml of methanol according to a sonvensional method, to give 75 mg of 4-amino-5-sloro-N- (3-sloro-lH-indole). 7-yl) -2-thiophenesulfonamide. 72 mg (0.20 mmol) of the prodrug was dissolved in 2 ml of tetrahydrofuran, and 18 μl of pyridine and 38 mg (0.2 mmol) of 5-methyl-3-pyridinesulfonyl sluride were added. After stirring at room temperature during noshe, the sap organisa was separated by adduction of ethyl acetate and slurry-acidic acid. Washes are water-soluble, an acid dissolution of sodium bisarbonate and water, brazed on magnesium sulfate and filtered. Then, the residue was purified by chromatography in silica gel solnum, to give 82 mg of the title substance. ^ -NMR (DMSO-de) d (ppm): 2.33 (3H, s), 6.76 (1H, d, J «7.7 Hz), 7.03 (1H, dd, J = 7.9, 7.7 Hz), 7.35 (1H, s), 7.38 (1H, d, J = 7.9 Hz), 7, 51 (1H, d, J = 2.7 Hz), 7.80 (1H, dd, J = 2.0, 1.5 Hz), 8.60 (1H, dd, J = 2.0, 0.4 Hz), 8.71 (1H, dd, J «1.5, 0.4 Hz), 10.35-10.40 (1H, m), 10.73-10.80 (1H, ansha), 11.16-11.19 (1H, m) Produssion Example lb 2- Amino-5-bromoguinoline Sufficiently stirred 2-Bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) for one minute. Then, diethyl phosphonate (25.8 ml) was added to the mixture (sianomethyl) phosphonate and the mixture was stirred for 2 additional hours. The agitation was stopped and the reassuring medley was left during the noshe. After this, ethyl acetate was added and the resulting mixture was stirred, followed by filtration. The filtrate was sonsented and the residue was purified by chromatography on silica gel solvate (ethyl acetate), to give 32 g of 3- (2-bromo-6-nitrophenyl) -2-propenenitrile (isomer E: isomer Z = 3: l). ^ -NMR (CDC13) d (ppm): 5.63 (d, J = 16.5 Hz, E-isomer, 1H), 5.81 (d, J = 10.8 Hz, Z-isomer, 1H), , 42-7.52 (m, E-isomer, 1H, Z-isomer, 2H), 7.56 (d, J = 16.5 Hz, E-isomer, 1H), 7.90-8.16 (m, isomer E, 2H, Z isomer, 2H). At sontinuation, ethanol (250 ml), tin (60 g) and distilled water (150 ml) were added to 32 g of 3- (2-bromo-6-nitrophenyl) -2-propenenitrile (isomer E: isomer Z = 3). : l), followed by salting out are agitation at 90 ° C. Dropwise was added dropwise to the shallow slurry dye mixture (256 ml), followed by agitation at the same temperature for 3 hours. After returning to room temperature, the sap was stripped and cooled to 0 ° C. The resulting solid was collected by filtration. He was given ammonia asuoso, and the mezsla was extracted are ethyl acetate. The extractate was concentrated and the residue was purified by chromatography on silica gel solvate (ethyl acetate) to give 5.0 g of the title suspension. XH-NMR (CDC13) d (ppm): 4.88 (2H, s ansho), 6.79 (1H, d, J = 9.3 Hz), 7.39 (1H, t, J = 8.9 Hz), 7.51 (1H, d, J = 8.9 Hz), 7.61 (1H, d, J = 8.9 Hz), 8.27 (1H, d, J = 9.3 Hz) . Produssion Example 2b 2-Amino-5-sloroguinoline The title compound was obtained from 2-chloro-6-nitrobenzaldehyde in the same manner as in Production Example lb. XH-NMR (CDC13) d (ppm): 5.25 (2H, broad s), 6.80 (1H, d, J = 9.7 Hz), 7.32 (1H, dd, J = 7.5) Hz, 1.5 Hz), 7.46 (1H, t, J = 7.5 Hz), 7.57 (1H, m), 8.30 (1H, d, J = 9.7 Hz, 1, 0 Hz). Production Example 3b 3-Carbetoxy-4-hydroxy-8-bromo-guinoline A mixture of 50 g (0.291 mole) of 2-bromoaniline and 63 g (0.291 mole) of diethylethoxymethylene malonate was heated at 100 ° C under redressed pressure for 3 hours and also at 200 ° C for 12 hours. After the reassumption was completed, the solid reassum mixture was washed with ethyl acetate and the crystals were resuspended by filtration and bent to give 50 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 1.26 (3H, t, J = 7.2 Hz), 4.21 (2H, s, J = 7.2 Hz), 7.34 (1H , t, J = 7.6 Hz), 8.03 (1H, dd, J = 1.6 Hz, 7.6 Hz), 8.15 (1H, dd, J = 1.6 Hz, 7.6 Hz), 8.43 (1H, s), 11.56 (1H, s). Produssion Example 4b 3-Carbetoxy-8-bromoguinoline A mixture of 2.5 g (8.4 mmol) of 3-sarbetoxy-4-hydroxy-8-bromoguinoline and 10 ml of phosphorus oxychloride was heated under reflux for one hour . After the reaction was complete, the phosphorus oxychloride was eliminated and the residue was purified by Gel de sílise NH, to give 2.6 g of a sloro- ^ ^ ^ ^ ^ ^ ^ ^ ^ Jj sompuesto. At sontinuation, 500 mg (1.6 mmol) of the sloro-somatose was dissolved in 20 ml of dioxane, 1 g of powdered sins and 3 ml of asbestos were admixed, followed by scaling at 65 ° C for 30 minutes. Ethyl acetate was added to the rejection solution, and the mixture was filtered through Celite. The filtrate was washed with brine, dried over magnesium sulfate and filtered. The residue was added with 1 ml of solid acetic acid, and the mixture was allowed to stand for 12 hours and then the acidic acetic acid was removed. The residue was subjected to silica gel column chromatography, and eluted with the solvent (ethyl acetate / n-hexane = 1/7), to give 180 mg of the title compound. XH-NMR (CDC13) d (ppm): 1.47 (3H, t, J = 7.2 Hz), 4.50 (2H, c, J = 7.2 Hz), 7.50 (1H, t , J = 7.6 Hz), 7.93 (1H, dd, J = 1.2 Hz, 7.6 Hz), 8.18 (1H, dd, J = 1.2 Hz, 7.6 Hz) , 8.85 (1H, d, J = 2 Hz), 9.57 (1H, d, J = 2 Hz). Produssion Example 5b 3-Amino-8-bromoguinoline 500 mg (1.8 mmol) of 3-sarbetoxy-8-bromoguinoline were admixed to gritty ethanol (10 ml) / dissolution 1? of αOH (10 ml) and the mixture was stirred at room temperature for 3 hours. The ethanol was removed and the residue neutralized is 1 HCl. The resulting solid was recovered by filtration, washed with water and sessed, to give 450 mg of an acid sarboxyl-lyso. At sontinuation, 450 mg (1.8 mmol) of the sarboxylyous acid was added to 25 ml of ters-butanol. In addition, 0.58 ml (2.7 mmol) of DPPA and 0.37 ml (2.7 mmol) of triethylamine were added to the mixture, followed by refluxing for 12 hours. The reassumption solution was shown, and the residue was subjected to silica gel chromatography and eluted to the solvent (ethyl acetate-n-hexane = 1-4), to give 352 mg of a somida amide. At sontinuation, 350 mg (1.1 mmol) of the somatose amide was added to a mixture of 4 ml of methanol / 2 ml of HCl salts. , and the mixture was stirred at room temperature for one hour. The solssion of reassión was alsalinized and ammonia was removed and extracted ethyl acetate. The sap organis were washed in brine, dried over magnesium sulfate and then sonsensed to give 240 mg of the title suspension. XH-NMR (DMSO-d6) d (ppm): 5.88 (2H, s), 7.13 (1H, d, J = 2.8 Hz), 7.24 (1H, dd, J = 7, 6 Hz, 8.4 Hz), 7.59-7.65 (2H, m), 8.49 (1H, d, J = 2.8 Hz). Produssion Example 6b 3-Amino-8-iodoguinoline The title compound was obtained from 2-iodoaniline in the same manner as in Produssion Examples (3b-5b). ^? - NMR (DMSO-de) d (ppm): 5.85 (2H, s), 7.07 (1H, d, J = 2.8 Hz), 7.10 (1H, t, J = 7 , 6 Hz), 7.62 (1H, dd, J = 1.2 Hz, 7.6 Hz), 7.90 (1H, dd, J = 1.2 Hz, 7.6 Hz), 8.45 (1H, d, J = 2.8 Hz). Produssion Example 7b 3-Amino-8-sianoguinoline The title compound was obtained from 2-sianoaniline in the same manner as in Produssion Examples (3b-5b). XH-NMR (DMSO-d6) d (ppm): 6.03 (2H, s ansho), 7.22 (1H, d, J = 2.8 Hz), 7.48 (1H, dd, J = 7 , 2 Hz, 8.4 Hz), 7.84 (1H, dd, J = 1.2 Hz, 8.4 Hz), 7.94 (1H, dd, J = 1.2 Hz, 8.4 Hz ), 8.57 (1H, d, J = 2.8 Hz). Produssion Example 8b 3 -Amino-8- (methylsulfonyl) uinoline The title compound was obtained in the same manner as in Produssion Examples (3b-5b). XH-NMR (CDC13) d (ppm): 6.00 (2H, s), 7.26 (1H, d, J = 2.4 Hz), 7.53 (1H, t, J = 7.2 Hz ), 7.91 (1H, dd, J = 1.6 Hz, 7.2 Hz), 7.96 (1H, dd, J = 1.2 Hz, 8.4 Hz), 8.58 (1H, d, J = 2.8 Hz). Produssion Example 9b 3-Amino-8-sloroguinoline The title compound was obtained in the same manner as in Produssion Examples (3b-5b). XH-NMR (DMSO-de) d (ppm): 5.90 (2H, s), 7.17 (1H, d, J = 2.8 Hz), 7.33 (1H, t, J = 7, 6 Hz), 7.46 (1H, d, J = 7.6 Hz), 7.58 ^ ¡^ ¡¡¡¡(1H, d, J = 7.6 Hz), 8.52 (1H, d, J = 2.8 Hz). Produssion Example 10b 3-Amino-8-trifluoromethylguinoline The title compound was obtained in the same manner as in Produssion Examples (3b-5b). ^ -NMR (DMSO-de) d (ppm): 5.94 (2H, s), 7.23 (1H, d, J = 2.8 Hz), 7.48 (1H, t, J = 7, 6 Hz), 7.69 (1H, d, J = 7.6 Hz), 7.91 (1H, d, J = 7.6 Hz), 8.55 (1H, d, J = 2.8 Hz ). Produssion Example 8-ethyl 8-chloro-4-vinylguinoline-3-sar-boxylate Tributylvinyltin (2.8 ml) and tetrakis-triphenylphosphine palladium (171 mg) were added to a toluene solution (20 ml) with 2, 0 g (7.4 mmol) of ethyl 4,8-disloroguinoline-3-sarboxylate obtained in the same manner as in Produssion Example 4b, followed by stirring for 2 hours, is refluxed. The reaction solution was filtered through Celite and the filtrate was filtered. Then, the residue was purified by silica gel chromatography, to give 1.92 g of the title substance. 2H-RM? (DMSO-de) d (ppm): 1.36 (3H, t, J = 7.6 Hz), 4.37 (2H, d, J = 7.6 Hz), 5.52 (1H, d, J = 18.0 Hz), 5.58 (1H, d, J = 16.4 Hz), 7.40 (1H, dd, J = 16.4, 18.0 Hz), 7.70 (1H, t, J = 8.0 Hz), 8.11 (1H, d, J = 8.0 Hz), 8.25 (1H, d, J = 8.0 Hz), 9.24 (1H, s) . Produssion Example 12b 3-Amino-8-sloro-4-vinylguinoline The title compound was obtained from ethyl 4-vinyl-8-sloroguinoline-3-sarboxylate in the same manner as in Produssion Example 5b. XH-RM? (DMSO-ds) d (ppm): 5.69 (1H, dd, J = 1.6, 18.0 Hz), 5.81 (2H, s), 5.84 (1H, dd, J = 1 , 6, 11.6 Hz), 6.91 (1H, dd, J = 11.6, 18.0 Hz), 7.38 (1H, t, J = 8.0 Hz), 7.52 (1H , dd, J = 1.2, 8.0 Hz), 7.85 (1H, dd, J = 1.2, 8.0 Hz), 8.60 (1H, s). Produssion Example 13b ethyl 7-amino-2-sloroguinoline-4-sarboxylate 43 g (231 mmol) of dietary oxaloasetate were added. - • & IiAili i i i i i i i i i i iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii * "~ ^" - t ** "A. ^. ^ k ^^ .. *, ..
The mixture was stirred at 25 ° C (231 mmol) of metaphenylenediamine and the mixture was stirred at 160 ° C for one hour. After cooling was present, the sristals washed are methanol. Phosphorus oxychloride (3.6 ml) was added to a solor of sloroform (30 ml), containing 3.0 g (13 mmol) of the crystals, followed by heating at reflux for one hour. After cooling, the mixture was poured into ice-water and alkalized to form a 1 N aqueous sodium hydroxide solution. Then, the crystals were resuspended by filtration and the tetrahydrofuran was added, and the filtrate was evaporated, to give 4.85 g of the title suspension. f XH-NMR (DMSO-de) d (ppm): 1.31-1.42 (3H, m), 4.34-4.46 (2H, m), 6.92 (1H, d, J = 2.4 Hz), 7.12 (1H, dd, J = 2.4, 9.2 Hz), 7.40 (1H, s), 8.21 (1H, d, J = 9.2 Hz) . Produssion Example 14b 2-Bienylthio-4-methoxypyridazine 843 mg (21 mmol, 55% asex) of sodium hydride in dimethyl sulfoxide (30 ml) was suspended. Under cooling are ice, 2.0 ml (16.7 mmol) of bensilmersaptane was added, followed by agitation for 10 minutes. 2.5 g (17.6 mmol) of 4-methoxy-2-sloropyridazine were added to the reaction mixture, followed by agitation at room temperature during noshe. A saturated asymmetric dissolution of ammonium slurry was admised to the reassessing mixture, followed by extrasysis are ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel, to give 1.63 g of the title substance. X H-NMR (DMSO-de) d (ppm): 3.98 (3 H, s), 4.48 (2 H, s), 7.12 (1 H, d, J = 8.8 Hz), 7.22 -7.26 (1H, m), 7.29-7.37 (2H, ra), 7.41-7.44 (2H, m), 7.57 (1H, d, J = 8.8 Hz ). Produssion Example 15b 2-Bienylthio-4-sarboxamidopyridine Thionyl slurry (120 ml) was added to 25 g (159 mmol) of 2-sloroisonisotinic acid, and the mixture was stirred while refluxing for 3 hours. After To cool it was, the mixture evaporated, to give a residue. A solution of tetrahydrofuran (200 ml) was poured out, the residue being kept in a solids mixture of aqueous ammonia (200 ml) and tetrahydrofuran (200 ml) under cooling being ice. After stirring under cooling they are ice for 15 minutes, the mezsla evaporated. The sristals were reslurried by filtration and washed with water, to give 22.6 g of green crystals. 4.2 ml (36 mmol) of bensyltiomersaptan and 10 g (77 mmol) of potassium sarbonate were added to a dissolution of dimethylformamide, stirring 5.13 g (32 mmol) of the green crystals, and the mixture was stirred while it was sagging. reflux for 3 hours. Water was added to the reassumption solution, and the mixture was extracted as ethyl acetate. The sapaorganisa was washed in brine, dried over magnesium sulfate and evaporated. Then, the residue was purified by silica gel chromatography, and the resultant syrups were washed with hexane, to give 6.3 g of the title suspension. XH-NMR (DMSO-de) d (ppm): 4.46 (2H, s), 7.22-7.33 (3H, m), 7.41 (2H, d, J = 7.2 Hz) , 7.49 (1H, dd, J = 1.6, 5.2 Hz), 7.67 (1H, s), 7.73 (1H, s), 8.21 (1H, s), 8, 58 (1H, d, J = 5.2 Hz). Produssion Example 16b 7-Amino-2-sloro-4-methyl-uroline 32 ml (251 mmol) of ethyl acetate-ethyl acetate were added to 27 g (251 mmol) of meta-phenylenediamine and the mixture was stirred at 200 ° C for one hour. After cooling was present, the sristals were washed in hexane. 15 ml of phosphorus oxychloride were added to 9.5 g (54 mmol) of the crystals, followed by refluxing for 2 hours. After cooling, the reassuring mixture was poured into ice-water and alsalinized, a saturated dissolution of saturated ammonia. The resulting crystals were reslurried by filtration and washed are water. The crystals were washed with methanol and the filtrate was evaporated, to give 4.85 g of the title compound. ^ tea ^^? g XH-RM (DMSO-de) d (ppm): 3.18 (3H, s), 5.95 (2H, s), 6.82 (1H, d, J = 2.4 Hz), 6.98 (1H, s), 7.01 (1H, dd, J = 2.4, 8.8 Hz), 7.76 (1H, d, J = 8.8 Hz). Produssion Example 17b 3, 4-Dihydroisoguinoline N-bromosussinimide (39.2 g) was added to a solution in methylene slurry (300 ml) containing 26.67 g (0.2 mol) of 1, 2, 3, 4 -tetrahydroisoguinoline under cooling with ice for 20 minutes. After stirring for 40 minutes, a 30% sodium hydroxide solution (130 ml) was added to the reassuming solution. The sap organelle was washed and the water was extracted and then dissolved in a 10% diluted form of slurry dichloride (200 ml). Washed sapa assaosa are methylene slurry, are alsalinized are asuous ammonia, and then extracted are methylene sluride. The ex-trastate was sessed over magnesium sulfate and then evaporated. The resulting residue was distilled (approximately 16 mmHg, 120 ° C), to give 21.5 g of the title substance as a bath. XH-NMR (DMSO-de) d (ppm): 2.66 (2H, t, J = 8 Hz), 3.62 (2H, td, J = 2 Hz, 8 Hz), 7.19-7, 21 (1H, m), 7.29-7.33 (1H, m), 7.35-7.40 (1H, m), 8.31 (1H, t, J = 2 Hz). Produssion Example 18b 7-Nitroisoguinoline 15 g of potassium nitrite were added to a dissolved sulfuric acid solution (70 ml) containing 18 g (0.14 mol) of 3,4-dihydroisoguinoline at -15 ° C for 20 minutes. After stirring at room temperature for one hour, the mixture was heated at 60 ° C for 40 minutes. The solution of reassumption was poured over ice-water and alsalinized is ammonia asuoso. The mixture is extracted are ethyl acetate, and the sap organisium is washed and brined over magnesium sulfate. After sonsentration, the residue was added to the desalin (100 ml), nitrobensen (100 ml) and 2 g of Pd Black, and the mixture was heated at 200 ° C during the noshe under nitrogen. The replication solution was washed with iaaMMík ^ < It is very easy to remove the ethyl acetate and then extracted it is a very fine 2N slurry. . The aspassed sap is washed with ethyl acetate and then an asoluous dissolution of sodium hydroxide was added. The resultant precipitate was resuspended by filtration and washed with water, to give 14.4 g of the title substance. XH-NMR (CDC13) d (ppm): 7.79 (1H, d, J = 5.6 Hz), 8.00 (1H, d, J = 9.2 Hz), 8.48 (1H, dd) , J = 2.4 Hz, 9.2 Hz), 8.75 (1H, d, J = 5.6 Hz), 8.96 (1H, d, J = 2 Hz), 9.48 (1H, s). Produssion Example 19b 4-Bromo-7-nitroisoquinoline 1.2 ml of ropy HBr and 3 ml of bromine were added to 1.6 g (9.19 mmol) of 7-nitroquinoline and the mixture was heated at 180 ° C for 5.5 hours. The reassumption solution extracted is ethyl acetate. The extrasto was washed succesively are a dissolving asuosa of sodium hydroxide, a dissolving asuosa of sodium thiosulfate and brine, was sesos on magnesium sulfate and sonsentró. Then, the resulting residue was purified by silica gel solvate chromatography (eluted is hexane-hexane: ethyl acetate = 4: 1), to give 500 mg of the title substance. XH-NMR (CDC13) d (ppm): 8.36 (1H, d, J = 9.2 Hz), 8.58 (1H, d, J = 2.4 Hz, 9.2 Hz), 8, 93 (1H, s), 8.96 (1H, d, J = 3.2 Hz), 9.38 (1H, s). Produssion Example 20b 7-Amino-4-bromoisoquinoline 66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline were dissolved in 1 ml of ethanol, 2 ml of tetrahydrofuran and 1 ml of water. 70 mg of iron powder and 140 mg of ammonium slurry were added to the mixture, followed by scaling at 50 ° C for 3 hours. A dissolution of sodium hydroxide was added to the reassumption solution, and the mixture was extracted to form sloroform. The sapa organelle was sessed over magnesium sulfate and filtered. The resulting residue was crystallized from isopropyl ether, to give 33 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 5.98 (2H, s), 6.97 (1H, d, J = 2.4 Hz), 7.31 (1H, dd, J = 2, 4 Hz, 8.8 Hz), 8.28 (1H, s), 8.89 (1H, s). Produssion Example 21b 6- (4-Toluenesulfonylamino) isoquinoline 6-aminoisoquinoline (3 was dissolved, 348 g, Synthesis, 733 (1975)) in pyridine (30 ml). The mixture was 4-toluenesulfonyl chloride (5.13 g), followed by agitation at room temperature during noshe. Water was added to it, and the mixture was extracted as ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystallized from ethanol, to give the title suspension (5.958 g, 85%) yellow-white silica. XH-NMR (DMSO-de) d (ppm): 2.28 (3H, s), 7.32 (2H, d, J = 8.2 Hz), 7.40 (1H, dd, J = 1, 6, 9.2 Hz), 7.55 (1H, s ansho), 7.67 (1H, d, J = 5.6 Hz), 7.74 (2H, d, J = 8.2 Hz), 7.97 (1H, d, J = 9.2 Hz), 8.36 (1H, d, J = 5.6 Hz), 9.10 (1H, s). Produssion Example 22b l-Chloro-6- (4-toluenesulfonylamino) -isoquinoline 6- (4-Toluenesulfonylamino) isoquinoline (3.0 g, Produssion Example 21b) was dissolved in sloroform (100 ml). Under cooling are ice, m-sloroperbenzoiso (2.57 g) was added, followed by agitation at room temperature during noshe. The solvent was evaporated, and the resultant crystals were washed diethyl ether, resuspended by filtration and bent, to give yellow slaro crystals. The sristals were suspended in sloroform (83 ml) and phosphorus oxyschloride (19 ml) was added, followed by refluxing for 5 hours. After cooling, the solvent was evaporated. The residue was alsalinized by adduction of a saturated aqueous sodium bicarbonate solution in an ice bath, and then the mixture was extracted with ethyl acetate. The extra was washed is brine and was anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel solnum, to give crude crystals of the title suspension (1.630 g, 49.40%). The ethanol crystals were recrystallized to give the title compound insoluble crystals. XH-NMR (DMSO-de) d (ppm): 2.29 (3H, s), 7.34 (2H, d, J = 8.0 Hz), 7.52 (1H, dd, J = 2, 0, 9.0 Hz), 7.65 <; 1H, d, J = 2.0 Hz), 7.76 (1H, d, J = 5.6 Hz), 7.77 (2H, d, J = 8.0 Hz), 8.14 (1H , d, J = 9.0 Hz), 8.16 (1H, d, J = 5.6 Hz). Produssion Example 23b 6-Amino-l-sloroisoquinoline l-Sloro-6- (4-toluenesulfonylamino) isoquinoline (3.323 g, Produssion Example 22b) was dissolved in sulfuric acid (30 ml), followed by agitation at room temperature during the noshe. The reaction solution was poured on ice, and alsalinized by adduction of an asoluous sodium hydroxide dissolution and potassium sarbonate sonination, followed by extrasysis are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.37 g, 76.81%), yellowish brown crystals. XH-NMR (DMSO-de) d (ppm): 6.23 (2H, s ansho), 6.76 (1H, s), 7.09 (1H, d, J = 9.6 Hz), 7, 37 (1H, d, J = 6.4 Hz), 7.89 (1H, d, J = 9.6 Hz), 7.90 (1H, d, J = 6.4 Hz). Produssion Example 24b 2-Chloro-1,6-naphthyridine 1,6-naphthyridine-2-one (1.0 g, J. Org Chem. 4744 (1990)) was dissolved in phosphorus oxychloride (19 ml), followed by refluxing at 120 ° C for 2 hours. After cooling, the solvent was evaporated, and the residue was alsalinized with water and potassium sarbonate. Then, the mixture is extracted are ethyl acetate, and the extra was washed is brine and brazed on anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (0.658 g, 58.45%) orange crystals. ^ -NMR (CDC13) d (ppm): 7.55 (1H, d, J = 8.8 Hz), 7.86 (1H, d, J = 6.0 Hz), 8.28 (1H, d , J = 8.8 Hz), 8.80 (1H, d, J = 6.0 . lk¿ t¿.í¡ m? Mk ^. »~. ** 7 & Hz), 9.29 (1H, s). Produssion Example 25b 2-Amino-1, 6-naphthyridine 2-chloro-1,6-naphthyridine (0.628 g, Produssion Example 22b) and asmous ammonia (40 ml) were eluted at 130 ° C for 11 hours in a tube serrated. After cooling, the mixture is extracted with ethyl acetate, and the extra is washed with brine and anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel solnum, to give the title suspension (0.497 g, 10 89.73%) somo sristales yellow slaro. XH-NMR (DMSO-de) d (ppm): 6.81 (1H, d, J = 8.8 Hz), 7.24 (1H, d, J = 5.8 Hz), 7.97 (1H , d, J = 8.8 Hz), 8.34 (1H, d, J = 5.8 Hz), 8.80 (1H, s). Produssion Example 26b N- (3-Nitrophenethyl) phthalimide. Alsohol 3-nitrophenetimise (15 g) was dissolved in tetrahydrofuran (225 ml). After adducing triphenylphosphine. { 26 g) and phthalimide (13.9 g), the mixture was cooled to ice and diethyl azodisarboxylate (15.5 ml) was added dropwise. After stirring at room temperature during a After 20 hours, the resulting crystals were resuspended by filtration, washed with diethyl ether and bent, to give N- (3-nitrophenethyl) phthalimide insoluble crystals. ^ -NMR (CDC13) d (ppm): 3.12 (2H, t, J = 7.4 Hz), 3.98 (2H, t, J = 7.4 Hz), 7.47 (1H, dd) , J = 8.0, 8.0 Hz), 7.60 (1H, d, J = 25 8.0 Hz), 7.72 (2H, m), 7.83 (2H, m), 8.09 (1H, d, J = 8.0 Hz), 8.12 (1H, s). Produssion Example 27b 3-Nitrophenethylamine N- (3-Nitrophenethyl) phthalimide obtained in Produssion Example 26b was suspended in ethanol (150 ml). It was adhered to 30 the hydrazine mixture (5.7 ml), followed by refluxing for one hour. The dissolution of reassessment dissolved completely, but the sristales presipitaron again. The crystals were filtered and washed are cold ethanol. Then, the solvent was evaporated, to give the stain of the Title (5,559 g, 99%) We are a yellow toilet. XH-NMR (CDC13) d (ppm): 2.87 (2H, t, J = 6.8 Hz), 3.04 (2H, t, J = 6.8 Hz), 7.48 (1H, dd) , J = 7.6, 8.4 Hz), 7.55 (1H, ddd, J-1,2, 1.6, 7.6 Hz), 8.08 (2H, m). Produssion Example 28b N-Asethyl-N- (3-nitrofenethyl) amine 3-Nitrophenethylamine (5.559 g, Produssion Example 25b) was dissolved in pyridine (33 ml), and asethyl sulphide (2) was added dropwise to it. 5 ml) under cooling are ice. After stirring at room temperature for 0.5 hr, the mixture was cooled to ice again. Water was added to it, and the mixture was extracted as ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, to give the title product (6.323 g, 91%) as a yellow product. ^ -NMR (CDC13) d (ppm): 1.97 (3H, s), 2.95 (2H, t, J = 7.0 Hz), 3.55 (2H, dt, J = 6.0, 7.0 Hz), 5.60 (1H, s ansho), 7.49 (1H, dd, J = 7.2, 8.0 Hz), 7.55 (1H, d, J = 7.2 Hz ), 8.07 (1H, s), 8.12 (1H, d, J = 8.0 Hz). Produssion Example 29b N-Asethyl-N- (3-aminophenethyl) amine N-Asethyl-N- (3-nitrophenethyl) amine (2.1 g, Produssion Example 28b) was dissolved in ethanol (40 ml). Iron powder (2.25 g), ammonium asetate (4.3 g) and water (20 ml) were added to the mixture, followed by refluxing for 1.5 hours. The solid was removed by filtration and washed is ethanol, and then the filtrate was evaporated patially. The residue is extracted are ethyl acetate, washed with brine and anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (1.723 g, 96%) as a yellow bath. XH-NMR (CDC13) d (ppm): 1.94 (3H, s), 2.72 (2H, t, J = 6.8 Hz), 3.50 (2H, dt, J = 6.0, 6.8 Hz), 6.53 (1H, s), 6.57 (1H, d, J = 8.0 Hz), 6.59 (1H, d, J = 7.2 Hz), 7.10 (1H, dd, J = 7.2, 8.0 Hz). Produssion Example 30b N-Asethyl-N- (3-ethoxysarbonylamino- phenethyl amine) phenyl amine N-Asethyl-N- (3-aminophenethyl) amine (1.7 g, Produssion Example 29b) was dissolved in pyridine (5 ml). Under cooling are ice, it was dropped dropwise ethyl sloroformate (1, 4 ml), followed by stirring at room temperature for one hour. Then, the mezsla cooled down is ice again and water was added to it. The mixture is extracted are ethyl acetate, and the extra was washed is brine and brazed on anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (2.358 g, 97%) as a yellow bath. ^ -RMN (CDC13) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 1.93 (3H, s), 2.76 (2H, t, J = 7.0 Hz ), 3.47 (2H, dt, J = 6.0, 7.0 Hz), 4.20 (2H, s, J = 7.2 Hz), 5.57 (1H, s ansho), 6, 86 (1H, d, J = 7.2 Hz), 7.21 (1H, dd, J = 7.2, 8.0 Hz), 7.28 (1H, d, J = 8.0 Hz), 7.29 (1H, s). Produssion Example 31b 6 -Ethoxyabonylamino-1-methyl-3,4-dihydroisoquinoline Using N-asethyl-N- (3-ethoxysarbonylaminophenethyl) amine (1.0 g, Produssion Example 30b), a synapse reaction was made according to they are the dessrito method in Heterosy-sles 31 (2), 341 (1990). After the reaction was complete, the remission dilution was poured on ice and alsalinized with potassium sarbonate. Then, the sol ution was extracted are ethyl acetate, and the extra was washed brine and brazed on anhydrous magnesium sulfate. The solvent was evaporated, to give the title slurry a brown sachet. XH-NMR (CDC13) d (ppm): 1.19 (3H, t, J = 7.2 Hz), 2.23 (3H, s), 2.60 (2H, t, J = 7.4 Hz ), 3.55 (2H, t, J = 7.4 Hz), 4.13 (2H, s, J = 7.2 Hz), 7.31 (1H, d, J = 6.8 Hz), 7.32 (1H, s), 7.34 (1H, d, J = 6.8 Hz). Produssion Example 32b 6-Ethoxysarbonylamino-l-methylisoquinoline í, * k? uá¡, M? k, »? . ".. ^ .. t ^ mAiijj ^ P-synene (100 ml) and palladium sarbon (0, S g) were added to 6-ethoxysarbonylamino-l-methyl-3,4-dihydroisoquinoline, followed by scaling are agitation to 195 ° C for one hour under nitrogen atmosphere. The filler was removed by filtration and washed with ethanol, and then the filtrate was evaporated to a minimum. After extracting they are roughly inorganic, the extra is alsalinized are potassium sarbonate and then extracted are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, to give the title filler (0.629 g, 69%, 2 stages) somo sristales yellow slaro. ^ -NMR (CDC13) d (ppm): 1.30 (3H, t, J = 7.2 Hz), 2.89 (3H, s), 4.26 (2H, s, J = 7.2 Hz), 7.40 (1H, d, J = 5.8 Hz), 7.56 (1H, dd, J = 1.6, 8.8 Hz) ), 7.99 (1H, d, J = 8.8 Hz), 8.05 (1H, d, J = 1.6 Hz), 8.30 (1H, d, J = 5.6 Hz), 8.37 (1H, s). Produssion Example 33b 6-Amino-l-methylisoguinoline 6-Ethoxysarbonylamino-l-methylisoguiinoline (0.629 g, Produssion Example 32b) was dissolved in ethanol (20 ml), to which an 8 N asylate hydroxide solution was added. sodium (6.8 ml), followed by refluxing for 1.5 hours. After cooling, the mixture was at room temperature, a saturated aqueous solution of ammonium slurry was added, and the mixture was extracted with ethyl acetate. The extra was washed is brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (0.311 g, 72%) yellow silica gel. ^ -NMR (CDC13) d (ppm): 2.81 (3H, s), 4.24 (2H, s ansho), 6.60 (1H, d, J = 2.0 Hz), 6.91 ( 1H, ddd, J = 1.6, 2.0, 8.8 Hz), 7.18 (1H, d, J = 5.6 Hz), 7.84 (1H, d, J = 8.8 Hz ), 8.16 (1H, dd, J = 1.6, 5.6 Hz). Produssion Example 34b Nt-Butoxysarbonyl-3-Nitrophene-N-methylamine 3-Nitrophenethylamine (4.559 g, Produssion Example 27b) was dissolved in tetrahydrofuran (130 ml), to which was added triethylamine (8.4 ml) and sodium disarbonate. di-t-butyl (6.6 g), followed by agitation at room temperature for 2 hours. After evaporating the solvent, brine was added and the mixture then extracted was ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (8.789 g, including impurities) as a yellow material. It was used in the next reassignment without additional purification. XH-NMR (CDC13) d (ppm): 1.53 (9H, s), 2.92 (2H, t, J = 7.6 Hz), 3.42 (2H, dt, J = 6.4, 6.8 Hz), 4.58 (1H, s ansho), 7.48 (1H, dd, J = 7.2, 8.0 Hz), 7.54 (1H, d, J = 8.0 Hz ), 8.07 (1H, s), 8.10 (1H, d, J = 7.2 Hz). Produssion Example 35b 3- (2-t-Butoxy-arbonylamine-ethyl) aniline The title compound (5.521 g, 76%) was obtained as a yellow sample using Nt-butoxyarbonyl-3-nitrophenethylamine (8.789 g, including impurities, Produssion 34b) in the same manner as in Produssion Example 170b. aH-NMR (CDCl 3) d (ppm): 1.44 (9H, s), 2.70 (2H, t, J = 7.4 Hz), 3.36 (2H, s ansho), 4.54 ( 1H, s ansho), 6.54 (1H, s), 6.57 (1H, d, J = 8.0 Hz), 6.60 (1H, d, J = 7.2 Hz), 8.10 (1H, dd, J = 7.2, 8.0 Hz). Produssion Example 36b 3- (2-Butoxysarbonylaminoethyl) -ethoxysarbonylaminobensen The title compound (0.320 g) was obtained as a yellow sample using 3- (2-t-butoxy-arylamino-ethyl-ethyl) -aniline (5.521 g, Produssion Example 35b) thereof way in Produssion Example 29b. It was used in the next reaction without additional purification. 2 H-NMR (CDC 13) d (ppm): 1.31 (3 H, t, J = 7.2 Hz), 1.43 (9 H, s), 2.77 (2 H, t, J = 7.4 Hz ), 3.67 (2H, s ansho), 4.22 (2H, s, J = 7.4 Hz), 4.55 (1H, s ansho), 6.52 (1H, s ansho), 6, 89 (1H, m), 7.24 (1H, m). Produssion Example 37b 3-Ethoxysarbonyl-aminophenethylamine hydroschloride 3- (2-t-Butoxysarbonylaminoethyl) ethoxys-bonilaminobensen (14.96 g, Produssion Example 36b) was dissolved in ethanol (15 ml), then a slurry-slurry was added. ml) under cooling are ice, followed by agitation at room temperature for 20 minutes. Acid slurhydride (12 ml) and ethanol (15 ml) were added, followed by stirring at room temperature for 20 minutes. Then, more slorhydride (20 ml) and ethanol (30 ml) were added, followed by stirring at room temperature for 30 minutes. After evaporation of the solvent (subjecting to azeotropy distillation together are toluene), the title compound (11.99 g) was obtained yellow-white somo-crystals. XH-NMR (DMSO-de) d (ppm): 1.22 (3H, t, J = 7.2 Hz), 2.82 (2H, m), 2.95 (2H, m), 4.10 (2H, s, J = 7.2 Hz), 6.86 (1H, d, J = 7.6 Hz), 7.20 (1H, dd, J = 7.6, 8.4 Hz), 7 , 31 (1H, d, J = 8.4 Hz), 7.36 (1H, s), 8.05 (2H, s ansho), 9.61 (1H, s). Produssion Example 38b 6-Aminoethyl-1,2,3,4-tetrahydroiso-guinoline The title compound (4.226 g, including impurities) was obtained as a yellow sample, using 3-ethoxysarbonylaminophenethylamine hydrosulphide (4.7 g) obtained in Produssion Example 39b of asiento they are the method dessrito in Chem. Farm. Bull. 42 (8), 1676 (1994). XH-NMR (CDC13) d (ppm): 1.29 (3H, t, J = 7.2 Hz), 2.68 (1H, s ansho), 2.83 (3H, m), 3.73 ( 2H, m), 4.20 (2H, s, J = 7.2 Hz), 6.77 (1H, s), 6.94 (1H, d, J = 8.4 Hz), 7.07 ( 1H, d, J = 8.4 Hz), 7.18 (1H, s ansho). Produssion Example 39b 6-Ethoxyarbonylaminoisoguinoline p-Synene (100 ml) and palladium sarbon (0.9 g) were added to 6-aminoethyl-1,2,3,4-tetrahydroisoguinoline (10 g, Produssion Example 38b) followed by salting out they are agita- I | at 195 ° C for one hour in a nitrogen atmosphere. The satallizer was removed by filtration, and the reassessed mixture was washed with ethanol. Then, the filtrate was evaporated, and the resulting crystals were washed diethyl ether and bent. The solvent was evaporated, to give the title compound (6.51 g, 66%) yellow silica gel. XH-NMR (CDC13) d (ppm): 1.36 (3H, t, J = 7.2 Hz), 3.74 (1H, m), 4.29 (2H, s, J = 7.2 Hz) ), 6.70 (1H, d, J = 2.0 Hz), 7.46 (1H, dd, J = 2.0, 8.8 Hz), 7.58 (1H, d, J = 6, 0 Hz), 7.90 (1H, d, J = 8.8 Hz), 8.04 (1H, s ansho), 8.46 (1H, d, J = 6.0 Hz), 9.13 ( 1H, s). Produssion Example 40b 6-Ethoxysarbonylaminoisoguinoline-N-oxide The title compound (293 mg) was obtained yellow slaro using 6-ethoxysarbonylaminoisoguinoline (250 mg, Produssion Example 39b) in the same manner as in the Produssion Example 22b. XH-NMR (DMSO-de) d (ppm): 1.25 (3H, t, J = 7.2 Hz), 4.26 (2H, s, J = 7.2 Hz), 7.61 (1H , dd, J = 2.0, 8.8 Hz), 7 79 (1H, d, J = 8.8 Hz), 7.81 (1H, d, J = 7.2 Hz), 8.04 ( 1H, dd, J = 2.0, 7.2 Hz), 8.79 (1H, s), 8.46 (1H, d, J = 6.0 Hz), 9.13 (1H, s). Produssion Example 41b l-Chloro-6-ethoxysarbon? Laminoiso-guinoline The title compound (173 mg, 60%, 2 eta-pas) was obtained by using yellow-slates using 6-ethoxycarbonylaminoisoguinoline-N-oxide (250 mg. ) in the same way as in Produssion Example 22b. XH-NMR (CDCl 3) d (ppm): 1.34 (3H, t, J = 7.2 Hz), 4.29 (2H, C, J = 7.2 Hz), 7.36 (1H, s) ansho), 7.50 (1H, d, J = 5.6 Hz), 7.52 (1H, dd, J = 2.4, 9.2 Hz), 8.11 (1H, m), 8, 19 (1H, d, J = 5.6 Hz), 8.22 (1H, d, J = 9.2 Hz). Produssion Example 42b 1-Methoxy-6-methoxysarbonyl-amino-guinoline L-sloro-6-ethoxysarbonylaminoisoguinoline was dissolved ÍÍÍÍ (2.27 g, Produssion Example 41b) in dimethyl sulfoxide (45 ml), then a 28% solvation of sodium methoxide (8.7 ml) was admised, followed by scaling are agitation at 110 ° C. ° C for 1.5 hours. After cooling, the mixture was at room temperature, a saturated aqueous solution of ammonium slurry was added, and the mixture was extracted with ethyl acetate. The extra was washed is brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title suspension (1.75 g, 84%) as a brown pad. XH-NMR (CDC13) d (ppm): 3.74 (3H, s), 4.03 (3H, s), 7.05 (1H, d, J = 5.8 Hz), 7.41 (1H , dd, J = 2.0, 9.2 Hz), 7.86 (1H, d, J = 5.8 Hz), 7.90 (1H, s ansho), 8.06 (1H, d, J = 9.2 Hz), 8.08 (1H, s ansho). Produssion Example 43b 6-Amino-l-methoxyisoguinoline The title compound (1.04 g, 99%) was obtained in brownish-gray somrosols, using 1-methoxy-6-methoxycarbonyl-aminoisoguinoline (1.75 g, Prod. 42b) and also methanol as solvent in the same manner as in Produssion Example 41b. XH-NMR (CDC13) d (ppm): 4.07 (3H, s), 4.07 (2H, s ansho), 6.78 (1H, d, J = 2.2 Hz), 6.88 ( 1H, dd, J = 2.2, 8.8 Hz), 6.95 (1H, d, J = 6.0 Hz), 7.84 (1H, d, J = 6.0 Hz), 8, 03 (1H, d, J = 8.8 Hz). Produssion Example 44b N-Propinyl- (3-Nitrophenethyl) Amine The title compound (3.070 g, 77%, including impurities) was obtained as a yellow sample, using 3-nitrophenethylamine (3.0 g, Produssion Example 27b) and propionyl slurry (2.5 ml) in the same manner as in Produssion Example 28b. ^ -NMR (CDC13) d (ppm): 1.14 (3H, t, J = 7.6 Hz), 2.19 (2H, c, J = 7.6 Hz), 2.96 (2H, t , J = 6.8 Hz), 3.56 (2H, dt, J = 6.4, 6.8 Hz), 7.49 (1H, dd, J = 7.6, 8.0 Hz), 7.55 (1H, d, J = 7.6 Hz), 8.07 (1H, s), 8.10 (1H, d, J = 8.0 Hz).
Example of Produssion 45b N-Propinyl- (3-aminophenethyl) amine N-propynyl- (3-nitrophenethyl) amine (3.070 g, Produssion Example 44b) was used to bring to taste the reassessment thereof way in Produssion Example 29b. The resulting residue was purified by silica gel solnum, to give the title suspension (0.857 g, 32%) as a yellow slaro aseil. XH-RM (CDC13) d (ppm): 1, 12 (3H, t, J = 7.6 Hz), 2.19 (2H, c, J = 7.6 Hz), 2.71 (2H, t, J = 6.8 Hz), 3.49 (2H, dt, J »6.0, 6.8 Hz), 5.56 (1H, s ansho), 6.52 (1H, s), 6.56 (1H, d, J = 7.6 Hz ), 6.56 (1H, d, J = 7.6 Hz), 7.09 (1H, dd, J = 7.6, 7.6 Hz). Produssion Example 46b N-Propinyl- (3-ethoxysarbonylamino-phenethyl) amine N-propynyl- (3-aminophenethyl) amine (0.857 g, Produssion Example 44b) was used to bring the reassess in the same manner as in the Produssion Example 30b. The resulting residue was purified by silica gel solnum, to give the title compound (0.747 g, 61%) as a yellowish-slaty material. a H-NMR (CDCl 3) d (ppm): 1.12 (3 H, t, J = 7.6 Hz), 1.30 (3 H, t, J = 7.0 Hz), 2.16 (2 H, s , J = 7.6 Hz), 2.78 (2H, t, J = 6, ß Hz), 3.50 (2H, dt, J = 6.0, 6.8 Hz), 4.21 (2H , s, J = 7.0 Hz), 6.67 (1H, s ansho), 6.87 (1H, d, J = 6.8 Hz), 7.00 (1H, s ansho), 7.22 (1H, dd, J = 6.8, 8.4 Hz), 7.26 (1H, d, J * 8.4 Hz), 7.28 (1H, s). Produssion Example 47b 6-Ethoxysarbonylamino-l-ethyliso-guinoline 6-Ethoxysarbonylamino-l-ethyl-3,4-dihydroisocyanine-guinoline was obtained using N-propynyl- (3-ethoxysarbonylaminophenethyl) amine (0.747 g, Example Produssion 46b) in the same manner as in Production Examples 31b-32b, and then the title compound (0.516 g, 75%, 2 steps) was obtained as a yellow oil.
The data of the intermediate and the title package are as follows. 6-Ethoxysarbonylamino-l-ethyl-3,4-dihydroisoquinoline XH-NMR (CDCl 3) d (ppm): 1.21 (3H, t, J = 7.6 Hz), 1.30 (3'H, t, J = 7.0 Hz), 2.66 (2H, t, J = 7.4 Hz), 2.74 (2H, s, J = 7.6 Hz), 3.64 (2H, t, J = 7.4 Hz), 4.23 (2H, s, J = 7.0 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.37 (1H, s), 7.43 (1H, d, J = 8.4 Hz), 7.79 (1H, s). 6-Ethoxyarbonylamino-l-ethylisoquinoline XH-NMR (CDC13) d (ppm): 1.32 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 7.6 Hz), 3.27 (2H, s, J = 7.6 Hz), 4.27 (2H, s, J = 7.0 Hz), 7.40 (1H, d, J = 6.0 Hz), 7, 52 (1H, dd, J = 2.0, 8.8 Hz), 7.89 (1H, s), 8.02 (1H, d, J = 2.0 Hz), 8.25 (1H, d) , J -8.8 Hz), 8.34 (1H, J = 6.0 Hz). Produssion Example 48b 6-Amino-l-Ethylisoquinoline The title compound (0.320 g, 88%) was obtained as yellow slaylike crystals using 6-ethoxysarbonylamino-1-ethylisoquinoline (0.516 g, Produssion Example 47b) in the same manner as in Produssion Example 33b. XH-NMR (CDC13) d (ppm): 1.31 (3H, t, J = 7.2 Hz), 3.21 (2H, O, J = 7.2 Hz), 4.20 (2H, s ansho), 6.82 (1H, d, J = 2.4 Hz), 6.95 (1H, dd, J = 2.4, 8.8 Hz), 7.21 (1H, d, J = 6 , 0 Hz), 7.94 (1H, d, J = 8.8 Hz), 8.24 (1H, d, J = 6.0 Hz). Produssion Example 49b l-Methoxy-4- (3-nitrophenyl) propane-1-ene Methoxymethylphosphonium slurry (31.1 g) was suspended in tetrahydrofuran (200 ml), then potassium t-butoxide (10.2 g) was added. g) under cooling are ice. When the reaction solution appeared red, a solution obtained by dissolving 3-nitroastophenone (lOg) in tetrahydrofuran (100 ml) was added dropwise using a pipette. After stirring at room temperature for 2.5 hours, a saturated saturated dissolution of ammonium slurry was quenched under ice cooling. They extracted the mezsla they are asetato ? AH? K., ^ L-d-ethyl, and the extra was washed are brine and p.sup. On anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column, to give the title compound (8.010 g) as a yellow layer. Produssion Example 50b 2- (3-Nitrophenyl) propanal Acidic slurry 2 N (150 ml) was added to l-methoxy-4- (3-nitrophenyl) propane-1-ene (8.010 g), followed by scaling is agitation to 80 ° C for 4 hours. Then, a slurry-dye (5 ml) was added, followed by refluxing for 2.5 hours. After cooling, the mixture was neutralized and dissolved in an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated to give the title suspension (7.531 g) as a yellow liquid. Produssion Example 51b 2- (3-Nitrophenyl) propane-ol 2- (3-nitrophenyl) propanal (7.531 g) was dissolved in ethanol (100 ml), then sodium borohydride (1.9 g) was added. under cooling they are ice, followed by agitation at room temperature for one hour. Brine was added to it, followed by extrasion, ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent was purified by silica gel solnum, to give the title compound (6.275 g, 57.19% in 3 steps) as a brown layer. XH-NMR (CDC13) d (ppm): 1.34 (3H, d, J = 6.8 Hz), 1.51 (1H, s ansho), 3.09 (1H, ts, J = 6.8 , 6.8 Hz), 3.78 (2H, d, J = 6.8 Hz), 7.50 (1H, dd, J = 7.6, 8.4 Hz), 7.60 (1H, ddd , J = 1.2, 1.6, 7.6 Hz), 8.10 (1H, ddd, J = 1.2, 2.4, 8.4 Hz), 8.13 (1H, dd, J = 1.6, 2.4 Hz). Produssion Example 52b 2- (3-Nitrophenyl) propylamine The title compound was obtained as a yellow l. > JJA .J.J., AAAiJJJMM tlio using 2- (3-nitrophenyl) propane-1-ol (1.908 g, Produssion Example 51b) in the same manner as in Production Examples 26b-27b. Production Example 53b l-t-Butoxisarbonylamino-2- (3-nitrophenyl) propane Reassay was carried out using 2- (3-nitrophenyl) pro-phenylamine obtained in Produssion Example 52b in the same manner as in Produssion Example 35b. The resulting residue was purified by silica gel solnum, to give the title title (2.626 g) we are a yellow salad. XH-NMR (CDC13) d (ppm): 1.31 (3H, d, J = 6.8 Hz), 1.40 (9H, s), 3.10 (1H, m), 3.26 (1H , m), 3.38 (1H, m), 7.49 (1H, dd, J = 7.6, 8.4 Hz), 7.56 (1H, d, J = 7.6 Hz), 8 , 08 (1H, s), 8.10 (1H, d, J = 8.4 Hz). Produssion Example 54b 2- (3-Aminophenyl) -1-t-butoxisar-bonylaminopropane The title compound was obtained as a yellow sample using obtained lt-butoxysarbonylamino-2- (3-nitrophenyl) propane (2.626 g) thereof as in the Produssion Examples 29b. Produssion Example 55b l-t-Butoxysarbonylamino-2- (3-ethoxysarbonylaminophenyl) propane Reassay was carried out using 2- (3-aminophenyl) -1-t-butoxysarbonylaminopropane obtained in the same manner as in Produssion Example 30b. The resulting residue was purified by column of silica gel, to give the title compound (2.960 g, 77.56% in 3 steps) as a brown oil. XH-NMR (CDCl 3) d (ppm): 1.25 (3H, d, J = 7.6 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.41 (9H, s) ), 2.90 (1H, m), 3.18 (1H, ddd, J = 4.2, 7.6, 9.2 Hz), 3.39 (1H, m), 4.42 (2H, c, J = 7.6 Hz), 4.45 (1H, s ansho), 6 87 (1H, s ansho), 6.94 (1H, m), 7.22 (3H, m). Produssion Example 56b 6-Ethoxysarbonylamino-4-methyl-1,2,3,4-tetrahydroisoquinoline The titer of the titer (2.967 g, crude) was obtained as a yellow solid using lt-butoxysarbonylamino-2- (3-ethoxysarbonylaminophenyl) propane (2.960 g, Production Example 55b) with the same method as in Production Examples 38b-39b. Production Example 57b 6-Etoxisarbonylamino-4-methyliso-quinoline The title compound (2.061 g, crude) was obtained as yellow slaro crystals using obtained 6-ethoxysarbonylamino-4-methyl-1,2,4,4-tetrahydroisoquinoline (2,967) g, gross) in the same manner as in Produssion Example 40b. XH-NMR (CDC13) d (ppm): 1.36 (3H, t, J = 7.2 Hz), 2.59 (3H, s), 4.30 (2H, s, J = 7.2 Hz ), 7.12 (1H, d, J = 2.0 Hz), 7.49 (1H, dd, J = 2.0, 8.8 Hz), 7.91 (1H, d, J = 8, 8 Hz), 8.12 (1H, s), 8.32 (1H, s), 9.00 (1H, s). Produssion Example 58b 6-Amino-4-methylisoquinoline Reassay was performed using obtained 6-ethoxysarbonylamino-4-methylisoquinoline (2.061 g, crude) in the same manner as in Produssion Example 30b. The resulting crystals were washed diethyl ether and bent, to give the title suspension (0.403 g, 27.75% in 4 steps). X H-NMR (CDCl 3) d (ppm): 2.48 (3 H, s), 4.18 (2 H, s ansho), 6.95 (1 H, d, J = 2.0 Hz), 7.00 ( 1H, dd, J = 2.0, 8.8 Hz), 7.76 (1H, d, J = 8.8 Hz), 8.19 (1H, s), 8.86 (1H, s). Produssion Example 59b 2- (3-Nitrophenyl) butane-1-ol The title substance (5.456 g, 50.08% in 3 steps) was obtained as a yellow sample using 3-nitropropi-none (10 g) are the same method as in Production Examples 52b-55b. XH-NMR (CDC13) d (ppm): 0.86 (3H, t, J = 7.4 Hz), 1.63 (1H, m), 1.85 (1H, m), 3.24 (1H , m), 3.83 (2H, m), 7.50 (1H, dd, J = 7.2, 8.0 Hz), 7.57 (1H, d, J = 8.0 Hz), 8 , 10 (1H, s), 8.13 (1H, d, J = 7.2 Hz).
Produssion Example 60b 2- (3-Nitrophenyl) butylamine The title compound (5.247 g) was obtained as a yellow sample using 2- (3-nitrophenyl) butane-1-ol (5.456 g, Produssion Example 59b) of the same as in Produssion Examples 26b-27b. Produssion Example 61b l-t-Butoxysarbonylamino-2- (3-nitrophenyl) butane
[0103] Sessing, reassignment was performed using obtained 2- (3-nitrophenyl) butylamine (5.247 g) in the same manner as in Produssion Example 27b. The resulting residue was purified by silica gel solnum, to give the title suspension (7.679 g) as a yellow-colored slat. XH-NMR (CDC13) d (ppm): 0.83 (3H, t, J = 7.4 Hz), 1.39 (9H, s), 1.63 (1H, m), 1.79 (1H , m), 2.84 (1H, m), 3.21 (1H, m), 3.52 (1H, m), 4.42 (1H, s ansho), 7.49 (1H, d, J = 7.6 Hz), 7.52 (1H, dd, J = 6.8, 7.6 Hz), 8.04 (1H, s), 8.10 (1H, d, J = 6.8 Hz ). Produssion Example 62b 2- (3-Aminophenyl) -lt-butoxisar-boniaminobutane The title compound (6.311 g, 85.40% in 4 steps) was obtained as a yellow sample using 1-t-butoxy-2-bonylamino-2 (3-nitrophenyl) butane (7.679 g) are the same method as in Produssion Example 29b. Produssion Example 63b l-t-Butoxysarbonylamino-2- (3-ethoxysarbonylaminophenyl) butane The title compound (8.230 g, crude) was obtained as an orange solid using the obtained mixture is the same method as in Produssion Example 30b. XH-NMR (CDCl 3) d (ppm): 0.81 (3H, t, J = 7.4 Hz) 1.31 (3H, t, J = 7.2 Hz), 1.40 (9H, s) , 1.55 (1H, m), 1.68, iH, m), 2.63 (1H, m), 3.14 (1H, ddd, J = 4.8, 8.8, 13.6 Hz), 3.52 (1H, m), 4.22 (2H, s, J = 7 , 2 Hz), 4.38 (1H, s ansho), 6 63 (1H, s ansho), 6.87 (1H, m), 7.23 (3H, m). Produssion Example 64b 6-Ethoxysarbonylamino-4-ethyl-1,2,3,4-tetrahydroisoquinoline The title compound was obtained as a brown sachet using lt-butoxysarbonylamino-2- (3-ethoxycarbonyl-aminophenyl) butane (8.230 g, crude, Produssion Example 63b, are the same method as in Produssion Examples 38b-39b Produssion Example 65b 6-Ethoxysarbonylamino-4-ethylisoquinoline The reassess was carried out using 6-ethoxysarbonylamino-4-ethyl-1 , 2, 3, -tetrahydroisoquinoline obtained (3, 0 g) in the same manner as in Produssion Example 40b. The resultant crude crystals were washed with ethanol / diethyl ether and bent, to give the title suspension as orange oristattes. ^ -NMR (DMSO-de) d (ppm): 1.27 (3H, t, J = 7.2 Hz), 1.28 (3H, t, J = 7.2 Hz), 2.91 (2H) , s, J = 7.2 Hz), 4.18 (2H, s, J = 7.2 Hz), 7.64 (1H, d, J = 8.8 Hz), 8.00 (1H, d , J = 8.8 Hz), 8.25 (1H, s), 8.27 (1H, s), 8.98 (1H, s), 10.12 (1H, s). Produssion Example 66b 6-Amino-4-Ethylisoquinoline Reassay was performed using 6-ethoxysarbonilarrtino-4-ethylisoquinoline in the same manner as in Produssion Example 30b. The resulting residue was purified by silica gel-NH column, and the resulting crude crystals were washed diethyl ether and bent, to give the title suspension (0.667 g) orange crystals. XH-NMR (CDC13) d (ppm): 1.35 (3H, t, J = 7.6 Hz), 2.92 (2H, s, J = 7.6 Hz), 4.17 (2H, s ansho), 6.99 (1H, d, J = 8.4 Hz), 7.00 (1H, s), 7.77 (1H, d, J = 8.4 Hz), 8.21 (1H, s), 8.86 (1H, s). Produssion Example 67b Methyl- (3-nitrobensil) diethyl malonate Sodium (0.7 g) was dissolved in ethanol (45 ml), then diethyl methyl-malonate (5.26 ml) and slurry 3- were added. nitrobensil (5 g), followed by salting out flow for 2 hours. The mixture was cooled down to ice and an asus dissolution of ammonium slurry was adhered to it, followed by extrasysis are ethyl acetate. The extra was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, to give the title suspension (9.724 g) as a yellow slaro asexide. XH-NMR (CDC13) d (ppm): 1.27 (6H, t, J = 7.2 Hz), 1.37 (3H, S), 3.32 (2H, s), 4.21 (4H , s, J = 7.2 Hz), 7.44 (1H, d, J - 7.6 Hz), 7.48 (1H, dd, J = 7.6, 7.6 Hz), 8.03 (1H, s), 8.11 (1H, d, J = 7.6 Hz). Example of Produssion 68b ethyl l-methyl-2- (3-nitrophenyl) propionate Diethyl methyl (3-nitrobensil) malonate obtained (9.724 g) was dissolved in dimethyl sulfoxide (30 ml), to which was then added water (0.54 ml) and lithium slurry (2.54 g), followed by agitation, are stripped at 190 ° C for 3.5 hours. After cooling it was, water was adhered to it, followed by extrassion are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, to give the title compound (5.071 g, 73.35% in 2 steps) as a brown layer. X H-NMR (CDCl 3) d (ppm): 1.20 (3 H, t, J = 7.2 Hz), 1.21 (3 H, d, J = 7.2 Hz), 2.79 (2 H, m ), 3.10 (1H, m), 4.10 (2H, s, J = 7.2 Hz), 7.45 (1H, dd, J = 7.6, 8.0 Hz), 7.52 (1H, d, J = 7.6 Hz), 8.06 (1H, s), 8.08 (1H, d, J = 8.0 Hz). Produssion Example 69b Asid l-methyl-2- (3-nitrophenyl) -propionisole Ethyl l-methyl-2- (3-nitrophenyl) propionate (5.071 g, Produssion Example 68b) was dissolved in ethanol (50 ml), The tannins were charged with a 5 N asuous dissolution of sodium hydroxide (43 ml), followed by refluxing for 2.5 hours. After cooling, the diethyl ether and water were adipose and the aqueous sap was separated. The sapa organelle was extracted as a saturated asphalt dissolution of bisar sodium bonato. The sumptuous sapas were sown, they were assidulated by adission of dilute slorhydride, and then they were extracted diethyl ether. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column, to give the title compound (2.918 g, 65.27%) as a red sachet. XH-NMR (CDC13) d (ppm): 1.24 (3H, d, J = 6.0 Hz), 2.83 (2H, s), 3.16 (1H, m), 7.47 (1H , dd, J = 7.2, 8.0 Hz), 7.54 (1H, d, J = 7.2 Hz), 8.08 (1H, s), 8.10 (1H, d, J = 8.0 Hz). Produssion Example 70b N-Bos-l-methyl-2- (3-nitro-enyl) -ethylamine. Sodium l-methyl-2- (3-nitrophenyl) propioniso (2.918 g, Produssion Example 69b) was dissolved in t-butanol. (36 ml), triethylamine (4.09 ml) and diphenylphosilazide were then added, followed by refluxing for 2.5 hours. After cooling, the solvent was evaporated. A saturated dissolution of saturated sodium bisarbonate was adhered to, followed by extrasysis are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. The solvent was evaporated, and ex. The resulting residue was purified by silica gel solnum to give the title compound (2.117 g, 54.14%) as yellow crystals. X H-NMR (CDCl 3) d (ppm): 1.13 (3 H, d, J = 6.8 Hz), 2.82 (1 H, m), 2.92 (1 H, m), 3.94 (1 H , s ansho), 7.47 (1H, dd, J = 7.2, 8.0 Hz), 7.54 (1H, d, J = 7.2 Hz), 8.05 (1H, s), 8.09 (1H, d, J = 8.0 Hz). Produssion Example 71b N-Bos-2- (3-aminophenyl) -1-methyl-ethylamine The reassess was carried out using N-Bos-l-methyl-2- (3-nitrophenyl) ethylamine (2.117 g, Example Produssion 70b) in the same manner as in Produssion Example 29b. After extracting, the resulting residue was purified by silica gel solnum, to give the title suspension (0.976 g, 51.63%) as a yellow liquid. Produssion Example 72b N-Bos-1-methyl-2- (3-ethoxysarbonyl-aminophenyl) ethylamine The title compound (1.173 g, crude) was obtained as a yellow sample using N-Bos-2- (3-aminophenyl) -1-methylethylamine (0, 976 g) are the same method as in Produssion Example 30b. It was used in the next reassignment without additional purification. XH-NMR (CDC13) d (ppm): 1.09 (3H, d, J = 6.4 Hz), 1.31 (3H, t, J = 7.2 Hz), 1.43 (9H, s) ), 2.62 (1H, dd, J = 6.8 Hz, 13.2 Hz), 2.82 (1H, m), 3.88 (1H, m), 4.22 (2H, s, J = 7.2 Hz), 4.38 (1H, m), 6.56 (1H, m), 6.89 (1H, d, J = 6.8 Hz), 7.18 (1H, s), 7.22 (1H, dd, J = 6.8, 8.0 Hz), 7.23 (1H, d, J = 8.0 Hz). Produssion Example 73b 2- (3-Etoxisar-bonylaminophenyl) -1-methylethylamine hydrochloride N-Bos-l-methyl-2- (3-ethoxysarbonylaminophenyl) -ethylamine (1.173 g, crude) was dissolved in ethanol (5.0 ml), then slurrydriso (5 ml) was adidased, followed by agitation at room temperature for 1.5 hours. Then, more slurry-dithrous (2.5 ml) was added, followed by agitation at room temperature for 2 hours. The solvent was evaporated to give the title compound (1.188 g, crude) as a yellow bath. It was used in the following reassessment without additional puri-fication. XH-NMR (DMSO-de) d (ppm): 1.03 (3H, d, J = 6.8 Hz), 1.22 (3H, t, J = 7.2 Hz), 2.55 (1H , m), 2.95 (1H, m), 3.32 (1H, m), 4.10 (2H, s, J = 7.2 Hz), 6.84 (1H, d, J = 7, 2 Hz), 7.21 (1H, dd, J = 7.2, 7.2 Hz), 7.29 (1H, d, J = 7.2 Hz), 7.35 (1H, s), 8 , 00 (1H, s ansho), 9.60 (1H, s). Produssion Example 74b 6-Ethoxysarbonylamino-3-methyl-1,2,3,4-tetrahydroisoquinoline Reassay was performed using 2- (3- hydrosulphide) ? m * tS¡aL? »k & ^ .. ¡k. ethoxysarbonylaminophenyl) -1-methylethylamine (1.148 g, Produssion Example 73b) according to the method of Chem. Farm »Bull. 42 (8), 1676 (1994). The prodrug was purified by a column of sylise-NH gel, to give the title suspension (0.441 g). XH-NMR (CDC13) d (ppm): 1.24 (3H, d, J = 6.4 Hz), 1.30 (3H, t, J = 7.2 Hz), 2.48 (1H, dd) , J = 10.0 Hz, 16.4 Hz), 2.75 (1H, dd, J = 3.6 Hz, 16.4 Hz), 3.01 (1H, m), 4.03 (2H, s wide), 4.21 (2H, c, J = 7.2 Hz), 6.66 (1H, s), 6.95 (1H, d, J = 8.4 Hz), 7.09 (1H , d, J = 8.4 Hz), 7.14 (1H, s). Produssion Example 75b 6-Ethoxysarbonylamino-3-methylisoquinoline The title compound (0.356 g) was obtained using 6-ethoxysarbonylamino-3-methyl-1, 2,3,4-tetrahydroisoquinoline ob-tenida (0.441 g) are the same method as in Produssion Example 39b. X H-NMR (CDCl 3) d (ppm): 1.34 (3 H, t, J = 7.2 Hz), 2.67 (3 H, a), 4.28 (2 H, s, J = 7.2 Hz ), 7.08 (lH, s ansho), 7.39 (1H, dd, J = 2.0, 8.8 Hz), 7.40 (1H, s), 7.85 (1H, d, J = 8.8 Hz), 7.94 (lH, s ansho), 9.05 (1H, s). Produssion Example 76b 6-Amino-3-methylisoquinoline The crude (0.182 g) crystals obtained using 6-ethoxysarbonylamino-3-methylisoquinoline obtained were washed. (0.356 g) are the same method as in Production Example 33b, diethyl ether and blended, to give the title suspension (93 g) yellow slaty crystals. X H-NMR (CDCl 3) d (ppm): 2.63 (3 H, s), 4.14 (2 H, s ansho), 6.77 (1 H, d, J = 2.0 Hz), 6.93 ( 1H, dd, J = 2.0, 8.8 Hz), 7.18 (1H, S), 7.72 (1H, d, J = 8.8 Hz), 8.9 Synthesis Example lb N- (8-Bromoquinoline-3-yl) -3-pyridine-sulfonamide 3-amino-8-bromoquinoline (300 mg, Produssion Example 5b) was dissolved in pyridine (5 ml), where 3-pyridinesulfonyl sluride (254) was added. mg), followed by agitation to .... «^ .. j ..,. ,, ^ ambient temperature for 30 minutes. After the reassumption was complete, the reassumption solution was poured over brine and extracted with ethyl acetate. The sap organza was blended on magnesium sulfate and then sonsented. The resulting crude crystals were washed with ethyl acetate and IPA, to give the title suspension (270 mg). XH-NMR (DMSO-de) d (ppm): 7.47 (1H, t, J = 8.0 Hz), 7.52-7.60 (1H, m), 7.99-8.03 ( 2H, m), 8.10 (1H, d, J = 2.4 Hz), 8.18- 8.22 (1H, m), 8.71 (1H, d, J = 2.4 Hz), 8.78 (1H, dd, J = 1.6 Hz, 4.8 Hz), 8.98 (1H, d, J = 2.4 Hz), 11.23 (1H, s ansho). Synthesis Example 2b N- (5-Bromoquinoline-2-yl) -5-methyl-3-pyridinesulfonamide The title compound was obtained from 2-amino-5-bromoquinoline (Example Prod. Lb) and slurry of 5- methyl-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.37 (3H, s), 7.58-7.72 (4H, m), 8.11 (1H, s ansho), 8.37 (1H , d, J = 9.6 Hz), 8.59 (1H, d, J = 1.2 Hz), 8.86 (1H, s ansho). Synthesis Example 3b 6-Amino-N- (8-bromoquinoline-3-yl) -3-pyridinesulfonamide The title compound was obtained from 3-amino-8-bromoquinoline (Produssion Example 5b) and slurry from 6- amino-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-d6) d (ppm): 6.40 (1H, d, J = 8.8 Hz), 6.93 (2H, S ansho), 7.44 (1H, t, J = 8 , 0 Hz), 7.65 (1H, dd, J = 2.4 Hz, 8.8 Hz), 7.96-7.99 (2H, m), 8.01 (1H, d, J = 2 , 4 Hz), 8.31 (1H, d, J = 2.4 Hz), 8.70 (1H, d, J = 2.4 Hz), 10.73 (1H, s ansho). Synthesis Example 4b N- (8-Bromoquinoline-3-yl) -4-sianosbensenosulfonamide The title compound was obtained from 3-ammo-8-bromoquinoline (Produssion Example 5b) and 4-siabensenosulfonyl slurry from the same way as in the Example of Synthesis lb. XH-NMR (DMSO-de) d (ppm): 7.46 (1H, t, J = 8.0 Hz), 7.96-8.07 (7H, m), 8.70 (1H, d, J = 2.4 Hz), 11.27 (1H, S ansho). Synthesis Example 5b 6-Chloro-N- (8-bromoguinoline-3-yl) -3- pyridinesulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 5b) and slurry of 6 - sloro-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. X H-NMR (DMSO-de) d (ppm): 7, 47 (1H, t, J = 8.0 Hz), 7.71 (1H, d, J = 8.4 Hz), 7.99-8.03 (2H, m), 8.10 (1H, d, J = 2.4 Hz), 8.20 (1H, dd, J = 8.4 Hz), 8.71 (1H, d, J = 2.4 Hz), 8.83 (1H, d, J = 2.4 Hz), 10.73 (1H, s ansho). Synthesis Example 6b N- (8-Bromoguinoline-3-yl) -4- (N-ethylsulfamoyl) bensenosulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 5b) and slurry 4 - (N-Ethylsulfamoyl) bensenosulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 0.82 (3H, t, J = 7.2 Hz), 2.69-2.76 (2H, m), 7.45 (1H, t, J = 8.4 Hz), 7.75 (1H, t, J = 5.6 Hz), 7.90-8.04 (7H, m), 8.70 (1H, d, J = 2.8 Hz), 11.18 (1H, s ansho). Synthesis Example 7b N- (8-Bromoguinoline-3-yl) -5-siane-2-pyridinesulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 5b) and slurry of 5- s-ano-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.46 (1H, t, J = 8.0 Hz), 7.95 (1H, d, J = 8.0 Hz), 8.01 (1H , d, J = 8.0 Hz), 8.11 (1H, d, J = 2.4 Hz), 8.21 (1H, d, J = 8.4 Hz), 8.57 (1H, dd , J = 2.0 Hz, 8.4 Hz), 8.79 (1H, d, J = 2.4 Hz), 9.14 (1H, d, J = 2.0 Hz), 11.49 ( 1H, s ansho).
A .., t.a¡ji..i "Í.Aiatii átgtjj-iJj ... A.j? Éia¿iBÍ¡É = iltt? M B« M¡iÉMlÉ I? - Synthesis Example 8b N- (8-Cyanoguinoline-3-yl) -3-pyridine sulfonamide The title compound was obtained from 3-amino-8-sianoguinoline (Produssion Example 7b) and 3-pyridinesulfonyl sluride from the same way as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.59 (1H, dd, J = 4.8 Hz, 8.0 Hz), 7.70 (1H, t, J = 8.0 Hz), 8.21-8.25 (3H, m), 8.33 (1H, d, J- 8.0 Hz), 8.77-8.79 (2H, m), 9.01 (1H, d, J »2.8 Hz), < 11.34 (1H, s ansho). Synthesis Example 9b N- (8-Cyanoguinoline-3-yl) -4-cyano-bensenosulfonamide The title compound was obtained from 3-amino-8-sianoguinoline (Produssion Example 7b) and 4-siabensenosulfonyl sluride from the same way as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.71 (1H, t, J = 8.0 Hz), 7.96-8.07 (4H, m), 8.18 (1H, d, J = 2.8 Hz), 8.24 (1H, d, J = 8.0 Hz), 8.31 (1H, d, J = 8.0 Hz), 8.78 (1H, d, J = 2.8 Hz), 11.37 (1H, s ansho). Synthesis Example 10b N- (5-Bromoguinoline-2-yl) -3-pyridine sulfonamide The title compound was obtained from 2-amino-5-bromoguinoline (Produssion Example lb) and 3-pyridinesulfonyl sluride from the same way as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.57-7.61 (3H, m), 7.70-7.72 (2H, m), 8.28 (1H, ansha), 8, 38 (1H, d, J = 9.6 Hz), 8.75 (1H, dd, J = 1.2 Hz, 4.8 Hz), 9.07 (1H, ansha). Synthesis Example llb N- (8-Bromogu? Nolin-3-yl) -5-indanesulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 5b) and slurry of 5- indanesulfonyl in the same manner as in the Example of thesis lb. XH-NMR (DMSO-de) d (ppm): 1.92-2.01 (2H, m), 2.81-2.86 (4H, m), 7.34 (1H, d, J = 8 , 0 Hz), 7.44 (1H, t, J = 8.0 Hz), 7.60 (1H, dd, J = 1.6 Hz, 8.0 Hz), 7.70 (1H, d, J = 1.6 Hz), 7.95 (1H, d, J = 8.0 Hz), 7.97 (1H, d, J = 8.0 Hz), 8.03 (1H, d, J = 2.4 Hz), 8.71 (1H, d, J = 2.4 Hz), 10.93 (1H, s ansho). Synthesis Example 12b N- (8-Yodoguinoline-3-yl) -N -asethyl-5-indolinesulfonamide The title compound was obtained from 3-amino-8-iodoguinoline (Produssion Example 6b) and N-Sluride asethyl-6-indolinasulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.11 (3H, s), 3.11 (2H, t, J = 8.4 Hz), 4.06 (2H, t, J = 8, 4 Hz), 7.28 (1H, t, J = 8.0 Hz), 7.65-7.68 (2H, m), 7.93-7.96 (2H, m), 8.05 ( 1H, d, J = 9.2 Hz), 8.22 (1H, dd, J = 1.2 Hz, 7.6 Hz), 8.64 (1H, d, J = 2.4 Hz), 10 , 87 (1H, s ansho). Synthesis Example 13b N- (8-Bromoguinoline-3-yl) -3-guinolinesulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 5b) and 3-guinolinesulfonyl slurry thereof way in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.38 (1H, t, J = 8.0 Hz), 7.70-7.74 (1H, m), 7.90-8.00 ( 3H, m), 8.07 (1H, d, J = 8.0 Hz), 8.13 (1H, d, J = 2.4 Hz), 8.19 (1H, dd, J = 0.8) Hz, 8.4 Hz), 8.75 (1H, d, J = 2.4 Hz), 9.00-9.01 (1H, m), 9.19 (1H, d, J = 2.4 Hz), 11.31 (1H, s ansho). Synthesis Example 14b N- (8-Bromoguinoline-3-yl) -N -acetyl-1,2,3,4-tetrahydroguinoline-6-sulfonamide The title compound was obtained from 3-amino-8-bromoguinoline ( Produssion Example 5b) and N-asethyl-1,2,3,4-tetrahydroguinoline-6-sulfonyl slurry in the same manner as in Synthesis Example lb.
XH-NMR (CDCl 3) d (ppm): 1.86-2.01 (2H, m), 2.77 (2H, t, J = 6.4) Hz), 3.65-3.76 (2H, m) Synthesis Example 15b N- (8-Yodoguinoline-3-yl) -4-isogui-nolinesulfonamide The title compound was obtained from 3-amino-8 -yodoguinoline (Produssion Example 6b) and 4-isoguinolinesulfonyl sluride in the same manner as in Example Synthesis lb. XH-NMR (DMSO-de) d (ppm): 7.26 (1H, t, J = 8.0 Hz), 7.82-7.86 (1H, m), 7.93-7.95 ( 1H, m), 7.98 (1H, d, J = 2.4 Hz), 8.02- 8.06 (1H, m), 8.19 (1H, dd, J = 1.2 Hz, 7 , 6 Hz), 8.27 (1H, d, J = 8.4 Hz), 8.59 (1H, d, J = 2.4 Hz), 8.67 (1H, d, J = 8.4 Hz), 9.12 (1H, s), 9.52 (1H, s), 11.57 (1H, s ansho). Synthesis Example 16b 4-Cyano-N- (8-iodoguinoline-3-yl) -bensenosulfonamide The title compound was obtained from 3-amino-8-iodoguinoline (Produssion Example 6b) and 4-siabensenosulfonyl sluride from the same way as in the Example of Synthesis lb. X H-NMR (DMSO-de) d (ppm): 7.31 (1 H, t, J = 8.0 Hz), 7.96-8.04 (6H, m), 8.26 (1H, dd, J = 1.2 Hz, 7.2 Hz), 8.65 (1H, d, J = 2.8 Hz), 11.24 (1H, s ansho). Synthesis Example 17b N- (8-Yodoguinoline-3-yl) -3-pyridine-sulfonamide The title compound was obtained from 3-amino-8-iodoguinoline (Produssion Example 6b) and 3-pyridinesulfonyl sluride from the same way as in the Example of Synthesis lb. XH-NMR (DMSO-de) d (ppm): 7.31 (1H, t, J = 8.0 Hz), 7.57-7.60 (1H, m), 7.99 (1H, d, J = 1.2 Hz, 8.4 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.18-8.21 (1H, m), 8.26 (1H, dd, 1.2 Hz, 7.2 Hz), 8.66 (1H, d, J = 2.8 Hz), 8.77 (1H, dd, J = 1.6 Hz, 4.8 Hz), 8.98 (1H, d, J = 2.8 Hz), 11.20 (1H, s ansho). Synthesis Example 18b N- (5-Bromoguinoline-2-yl) -4-sia- . ^. ^^^? ^ t ^ M? á ^^? Mk3 ^^^. ^^ M ^ Ak ^,?. ^ T, .j »41 ^ .1.1 bensenosulfonamide The title compound was obtained from 2-amino-5-bromoguinoline (Example Prod. Lb) and slurry of 4-siabensenosulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.57-7.73 (4H, m), 8.00-8.08 (4H, m), 8.38 (1H, d, J = 8 , 8 Hz). Synthesis Example 19b N- (8-Bromoguinoline-3-yl) -6-ethyl-3-pyridine sulfonamide. Pyridine (0.5 ml) and a methylene slurry (0.5 ml) solution were added containing a slurry of 6-8. ethyl-3-pyridinesulfonyl (30 ml) to 3-amino-8-bromoguinoline (18 mg, Produssion Example 5b) at 0 ° C. After stirring at room temperature for 30 minutes, water was added and the mixture was extracted with ethyl acetate. The extract was purified by preparative TLC (hexane-ethyl acetate = 1: 1), to give the title compound (20 mg). XH-NMR (CDC13) d (ppm): 1.25 (3H, t, J = 7.5 Hz), 2.70 (2H, c, J = 7.50 Hz), 7.34-7.98 (5H, m), 8.19 (1H, d, J = 3.3 Hz), 8.54 (1H, S), 8.83 (1H, d, J = 3.3 Hz). Synthesis Example 20b 4-Chloro-N- (5-sloroguinoline-2-yl) bensenosulfonamide Pyridine (1 ml) and 4-slorobensenosulfonyl slurry (255 mg) were added to 2-amino-5-sloroguinoline (119 mg, Example Produssion 2b) at room temperature, followed by agitation at room temperature for 3 days. Then, water was added, followed by extras are ethyl acetate. The ethyl acetate sheet was blended on sodium sulfate and filtered. Then, the resulting solid was wd with methanol, to give the title suspension (20 mg). XH-NMR (CDC13) d (ppm): 6.96 (1H, d, J = 9.7 Hz), 7.34 (1H, d, J = 8.4 Hz), 7.42-7.48 (3H, m), 7.54 (1H, t, J = 8.4 Hz), 7.94 (2H, d, J = 6.3 Hz), 8.29 (1H, d, J = 9, 7 Hz).
Synthesis Example 21b N- (8-Chloroginolin-3-yl) -6-ethyl-3-pyridinesulfonamide The title compound was obtained from 3-amino-8-sloroguinoline (Produssion Example 9b) and slurry from 6- ethyl-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 1.28 (3H, t, J = 8.3 Hz), 2.86 (2H, s, J = 8.3 Hz), 7.24 (1H, d , J = 8.0 Hz), 7.49 (1H, t, J = 8.0 Hz), 7.73 (1H, d, J = 8.0 Hz), 7.78 (1H, d, J = 8.0 Hz), 7.95 (1H, dd, J = 8.0 Hz, 2.1 Hz), 8.18 (1H, d, J = 2.5 Hz), 8.67 (1H, d, J = 2.5 Hz), 8.93 (1H, d, J = 2.1 Hz). Synthesis Example 22b N- (5-Chloroglinin-2-yl) -6-ethyl-3-pyridinesulfonamide The title compound was obtained from 2-amino-5-sloroguinoline (Produssion Example 2b) and slurry from 6- ethyl-3-pyridinesulfonyl in the same manner as in Synthesis Example lb. X H-NMR (CDCl 3) d (ppm): 1.32 (3 H, t, J = 8.3 Hz), 2.89 (2 H, C, J = 8.3 Hz), 6.97 (1 H, d , J = 9.4 Hz), 7.29 (1H, d, J = 8.0 Hz), 7.35 (1H, d, J = 8.0 Hz), 7.44 (1H, d, J = 8.0 Hz), 7.56 (1H, t, J = 8.0 Hz), 8.18 (1H, dd, J = 8.0 Hz, 2.6 Hz), 8.30 (1H, d, J = 9, 4 Hz), 9.10 (1H, d, J = 2.6 Hz). Synthesis Example 23b N- (8-Chlorogolinin-3-yl) -bensenosulfonamide The title compound was obtained from 3-amino-8-sloroguinoline (Produssion Example 9b) and bensenosulfonyl sluride in the same manner as in the Synthesis Example lb. XH-NMR (DMSO-dg) d (ppm): 7.30-7.48 (6H, m), 7.84 (2H, d, J = 7.4 Hz), 8.11 (1H, d, J = 3.1 Hz), 8.66 (1H, d, J = 3.1 Hz). Synthesis Example 24b 4-Cyano-N- (5-sloroguinoline-2-yl) -bensenosulfonamide The title compound was obtained from 3-amino-8-bromoguinoline (Produssion Example 2b) and slurry 4- sianobensenosulfonyl in the same manner as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 6.96 (1H, d, J = 9.5 Hz), 7.35 (1H, d, J = 8.7 Hz), 7.45 (1H, d , J = 8.7 Hz), 7.57 (1H, t J = 8.7 Hz), 7.78 (2H, d, J = 8.9 Hz), 8.10 (2H, d, J = 8.9 Hz), 8.33- (1H, d, J = 9.5 Hz). Synthesis Example 25b N- (5-Chloroglinin-2-yl) -4-ethyl-bensenosulfonamide The title compound was obtained from 2-amino-5-sloroguinoline (Produssion Example 2b) and 4-toluenesulfonyl sluride from the same way as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 2.41 (3H, s), 6.98 (1H, d, J = 9.3 Hz), 7.28 (2H, d, J = 8.2 Hz ), 7.35 (1H, d, J = 7.9 Hz), 7.41 (1H, d, J = 7.9 Hz), 7.53 (1H, t, J = 7.9 Hz), 7.88 (2H, d, J = 8.2 Hz), 8.26 (1H, d, J = 9.3 Hz). Synthesis Example 26b N- (5-Chlorogolinin-2-yl) -4-sulfamoylbensenosulfonamide The title compound was obtained from 2-amino-5-sloroguinoline (Produssion Example 2b) and 4-sulfamoylbensenosulfonyl slurry thereof way in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 7.42-7.49 (3H, m,), 7.58 (1H, t, J «8.0 Hz), 8.00-8.12 (4H , m,) 8.39 (1H, d, J = 9.3 Hz). Synthesis Example 27b N- (5-Bromoguinoline-2-yl) -4- (N-ethylsulfamoyl) bensenosulfonamide The title compound was obtained from 2-amino-5-sloroguinoline (Produssion Example 2b) and slurry 4 - (N-Ethylsulfamoyl) bensenosulfonyl in the same manner as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 1.14 (3H, t, J = 7.5 Hz), 3.01-3.09 (2H, m), 7.08 (1H, d, J = 9.5 Hz), 7.42 (1H, dd, J = 7.6 Hz, 1.3 Hz), 7.49 (1H, t, J = 7.6 Hz), 7.65 (1H, dd , J = 7.6 Hz, 1.3 Hz), 7.96 (2H, d, J = 8.7 Hz), 8.10 (2H, d, J = 8.7 Hz), 8.31 ( 1H, d, J = 9.5 Hz). Synthesis Example 28b 3-Cyano-N- (8-slorogininoline-3-i1) bensenosulfonamide The title compound was obtained from 3-amino-8-sloroguinoline (Produssion Example 9b) and 3-siabensenosulfonyl sluride from the same way as in Example dít Synthesis lb. XH-NMR (CDC13) d (ppm): 7.52 (1H, t, J = 7.9 Hz), 7.59 (1H, t, J = 7.9 Hz), 7.72-7.86 (3H, m), 8.00 (1H, d, J = 7.9 Hz), 8.13 (1H, d, J = 3.2 Hz), 8.16 (1H, s), 8.64 (1H, d, J = 3.2 Hz).
Synthesis Example 29b N- (8-Chlorogolinin-3-yl) -3-ethenesulfonamide-3-ethethyl ester The title compound was obtained from 3-amino-8-sloroguinoline (Produssion Example 9b) and 3-toluenesulfonyl slurry thereof way in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 2.35 (3H, s), 7.16-7.79 (7H, m), 8.09 (1H, d, J = 2.7 Hz), 8 , 65 (1H, d, J = 2.7 Hz). Synthesis Example 30b N- (8-Chlorogolinin-3-yl) -3-sulfaraoylbensenosulfonamide The title compound was obtained from 3-amino-8-sloroguinoline (Produssion Example 9b) and 3-sulfamoylbensenosulfonyl sluride from the same way as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 7.46 (1H, t, J = 7.6 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.58-7.78 (2H, m), 8.00 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 7.6 Hz), 8.14 (1H, d, J = 2, 8 Hz), 8.47 (1H, s), 8.59 (1H, d, J = 2.8 Hz). Synthesis Example 31b N- (8-Methyl-2-yl-3-yl) -3-pyridine-sulfonamide 562 mg of green crystals were obtained using 1.02 g * (5.2 mmol, Produssion Example 16b) of 7-amino- 2-sloro-4-methyl-zoline and 0.9 g (5.2 mmol) of 3-pyridinesulfonyl sluride in the same manner as in Example Mk ^ k, k ^^^. ^ I ^ 1¡ ^.? .. M ^ t ^^ mitM .. ^ cák ^ Synthesis lb. Methanol (4 ml), tetrahydrofuran (4 ml) and palladium sarbon 10% (5 mg) to 102 mg (0.29 mmol) were added to the blast crystals, followed by agitation for 6 hours under hydrogen atmosphere. The solusion of reassurance was filtered through Celite, and then evaporated. The residue was washed with ethyl acetate, to give 65 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 2.82 (3H, s), 7.64-7.66 (2H, ra>, 7.73 (1H, d, J = 5.2 Hz ), 8.03 (1H, s), 8.30-8.35 (2H, m), 8.82 (1H, dd, J = 1.2, 4.8 Hz), 9.00 (1H, d, J = 5.2 Hz), 9.11 (1H, d, J = 2.0 Hz) Synthesis Example 32b N- (8-Methyzoline-3-yl) -4-cyano-bensenosulfonamide 358 were obtained mg of blast crystals using 305 mg (1, 58 mmol, Produssion Example 16b) of 7-amino-2-sloro-4-methyl-uroline and 0.48 g (2.4 mmol) of 4-siabensenosulfonyl sluride in the same manner as in Synthesis Example lb. Acetic acid (6 ml), water (2 ml) and zins (122 mg) were added to 140 mg (0.38 mmol) of the white crystals, followed by agitation at 60 ° C for 15 minutes. After the reassolution solution was filtered through Celite, a saturated aqueous sodium bisarbonate dissolution was adhered, followed by extrasysis are ethyl acetate. The sap organis were washed in brine, blended on magnesium sulfate and filtered. Then, the residue was purified by silica gel chromatography, to give 82 mg of the title suspension. XH-NMR (DMSO-de) d (ppm): 2.60 (3H, s), 7.26 (1H, dd, J = 1.2, 4.4 Hz), 7.41 (1H, dd, J = 2.4, 8.8 Hz), 7.64 (1H, d, J- 2.4 Hz), 7.97-8.06 (1H, m), 7.98 (2H, d, J = 8.4 Hz), 8.04 (2H, d, J = 8.4 Hz), 8.66 (1H, d, J = 4.4 Hz), 11.06 (1H, s). Synthesis Example 33b N- (6-Chloro-8-sianoguinoline-3-ll) -3-pyridinesulfonamide 764 mg of green crystals were obtained using 3.0 mg (13 mmol, Produssion Example 13b) of 7-amino-2 - ,,, ^. ,, .. ^. ^ ^, ..j.A ^ .A ^ á.
Ethyl sloroquinoline-4-sarboxilate and 2.3 g (13 mmol) of 3-pyridinesulfonyl sluride in the same manner as in Synthesis Example lb. A 1 N sodium hydroxide solution (0.5 ml) was added to a dissolution in ethanol (6 ml) of 108 mg (0.28 mmol) of the glass panes, followed by stirring during noshe. An asuosa dissolusión 1 N of acid slorhídriso to the solusion of reassión was adhered, followed by extrassion are ethyl acetate two veses. The sapa organelle was washed, brine, blended on magnesium sulfate and filtered, to give a residue. Under cooling are ice, oxalyl sluride (0.04 ral) and a droplet of dimethylformamide were added to a tetrahydrofuran (10 ml) solution to dissolve the residue, followed by agitation at room temperature for 30 minutes. After 30 minutes, a saturated aqueous solution of ammonia (5 ml) was added, followed by agitation for 10 additional minutes. Brine was added to the reaction solution, followed by extrasysis are ethyl acetate. The sapa organelle was sessed over magnesium sulfate and sonsented to give a residue. Under cooling are ice, pyridine (0.06 ml) and anhydride of the trifluoroacetic acid (0.05 ml) were added to a tetrahydrofuran solution (6 ml) with the residue being kept, followed by stirring at room temperature for 30 minutes. Brine was added to the solution of reassess, followed by extrassion are ethyl acetate. The sapa organelle was sessed over magnesium sulfate and filtered. The residue was purified by silica gel chromatography to give 37 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 7.62-7.66 (1H, m), 7.68-7.72 (2H, m), 8.08 (1H, d, J = 8 , 8 Hz), 8.23 (1H, s), 8.26-8.29 (1H, m), 8.81 (1H, dd, J = 1.6, 4.8 Hz), 9.04 (1H, d, J = 2.4 Hz). Synthesis Example 34b N- (8-Chloroquinoline-3-yl) -4-siane-bensenosulfonamide 58 mg of the title compound was obtained using 38 Mb-t? Toto-riiiiii mil mttd m'mii mi mi mg (0.21 mmol) of 3-amino-8-sloroquinoline (0.21 mmol, Produssion Example 9b) and 43 mg (0.21 mmol) of 4-siabensenosulfonyl sloride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.55 (1H, t, J = 7.6 Hz), 7.84 (1H, d, J = 7.6 Hz), 7.95 (1H , t, J = 7.6 Hz), 7.99 (2H, d, J = 8.8 Hz), 8.04 (2H, d, J = 8.8 Hz), 8.09 (1H, d , J = 2.8 Hz), 8.73 (1H, d, J = 2.8 Hz), 11.39 (1H, s). Synthesis Example 35b N- (8-Chloroquinoline-3-yl) -4- (N-ethyl-sulfamoyl) bensenosulfonamide 36 mg of the title compound was obtained using 36 mg (0.19 mmol, Produssion Example 9b) of 3 -amino-8-sloroquinoline and 52 mg (0.19 mmol) of 4- (N-ethylsulfamoyl) bensenosulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 0.84 (3H, t, J = 7.2 Hz), 2.78-2.71 (2H, m), 7.54 (1H, t, J = 7.6 Hz), 7.77 (1H, t, J = 6.0 Hz), 7.83 (1H, t, J = 7.6 Hz), 7.92-7.95 (1H, m), 7.93 (2H, d, J = 8.8 Hz), 8.03 (2H, d, J = 8.8 Hz), 8.07 (1H, d, J = 2.4 Hz) , 8.73 (1H, d, J = 2.4 Hz), 11.20 (1H, s). Synthesis Example 36b N- (8-Chloroquinoline-3-yl) -3-pyridinesulfonamide 29 mg of the title compound were obtained using 33 mg (0.19 mmol, Produssion Example 9b) of 3-amino-8-sloroquinoline and 33 mg (0.19 mmol) of 3-pyridinesulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.54 (1H, t, J = 7.6 Hz), 7.60 (1H, dd, J = 4.8, 7.6 Hz), 7 , 81 (1H, d, J = 7.6 Hz), 7.94 (1H, d, J = 7.6 Hz), 8.09 (1H, d, J = 2.8 Hz), 8.19 -8.26 (1H, m), 8.72 (1H, d, J = 2.8 Hz), 8.77 (1H, d, J = 1.6, 4.8 Hz), 9.00 ( 1H, d, J = 2.8 Hz), 11.46 (1H, s). Synthesis Example 37b N- (8-Chloroquinoline-3-yl) -5-ethylsulfamoyl-2-pyridinesulfonamide > - • - tr-iHHVliTflilrtJ 10 mg of the title compound was obtained using 30 mg (0.17 mmol, Produssion Example 9b) of 3-amino-8-sloroquinoline and 95 mg (0.34 mmol) of 5-ethylsulfamoyl -2-slorosulfonylpyridine in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 0, 88 (3H, t, J = 7.6 Hz), 2.79-2.86 (2H, m), 7.55 (1H, t, J = 7.6 Hz), 7.85 (1H, t, J = 7.6 Hz), 7.94 (1H, d, J = 7.6 Hz), 8.00 (1H, t, J = 6.4 Hz), 8.16 (1H, d, J = 2.8 Hz), 8.27 (1H, d, J = 8.0 Hz), 8.41 (1H, d, J = 2.4, 8.0 Hz), 8.84 (1H, d, J = 2.8 Hz), 9.04 (1H, d, J = 2.4 Hz), 11.47 (1H, s). Synthesis Example 38b N- (8-Trifluoromethylquinoline-3-yl) -4-siabensenosulfonamide 59 mg of the title compound was obtained using 35 mg (0.17 mmol, Produssion Example 10b) of 3-amino-8-trifluoromethylquinoline and 37 mg (0.18 mmol) of sloride 4-siabensenosulfonyl in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.71 (1H, t, J = 7.6 Hz), 8.03-8.09 (5H, m), 8.19 (1H, d, J = 2.4 Hz), 8.30 (1H, d, J = 7.6 Hz), 8.78 (1H, d, J = 2.4 Hz), 11.72 (1H, s). Synthesis Example 39b N- (8-Trifluoromethylquinoline-3-yl) -4- (N-ethylsulphamoyl) bensenosulfonamide 60 mg of the title compound was obtained using 35 mg (0.17 mmol, Produssion Example 10b) of 3-amino -8-trifluoromethylquinoline and 56 mg (0.20 mmol) of 4- (N-ethylsulfamoyl) bensenosulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-d6) d (ppm): 0.83 (3H, t, J = 7.2 Hz), 2.71-2.78 (2H, m), 7.69 (1H, t, J = 8.0 Hz), 7.76 (1H, t, J = 5.6 Hz), 7.93 (1H, d, J = 8.8 Hz), 8.04-8.07 (3H, m), 8.13 (1H, d, J = 2.8 Hz), 8.25 (1H, d, J = 8.0 Hz), 8.75 (1H, d, J = 2.8 Hz) , 11.28 (1H, s). Synthesis Example 40b N- (8-Trifluormethylquinoline-3-iI) -3- i ^^ Í ^ t¡! lJl? HJÍ ^ jjj ^ fckg & pyridinesulfonamide 71 mg of the title compound were obtained using 45 mg (0.21 mmol, Produssion Example 10b) of 3-amino-8-trifluoromethylquinoline and 45 mg (0.25 mmol) of 3-pyridinesulfonyl sluride in the same manner that in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.59-7.63 (1H, m), 7.70 (1H, t, J = 7.6 Hz), 8.06 (1H, d, J = 7.6 Hz), 8.20 (1H, d, J = 2.8 Hz), 8.23-8.24 (1H, m), 8.30 (1H, d, J = 7.6 Hz), 8.76 (1H, d, J = 2.8 Hz), 8.79 (1H, dd, J = 1.6, 4.8 Hz), 9.03 (1H, d, J = 2 , 0 Hz), 11.64 (1H, s). Synthesis Example 41b N- (8-Chloroginin-3-yl) -1, 2, 3, 4-tetrahydro-6-naphthalenesulfonamide 46 mg of the title compound was obtained using 33 mg (0.19 mmol, Produssion Example 9b ) of 3-amino-8-sloroquinoline and 73 mg (0.22 mmol) of 6-slorosulfonyl-1,2,3,4-tetrahydronaphthalene in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 1.68 (4H, ansha), 2.71 (4H, ansha), 7.20 (1H, t, J = 8.4 Hz), 7.52 (1H, t, J = 7.6 Hz), 7.53 (1H, 'dd, J = 2.0, 8.4 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.80 (1H, d, J »7.6 Hz), 7.93 (1H, d, J = 7.6 Hz), 8.06 (1H, d, J = 2.4 Hz), 8, 73 (1H, d, J = 2.4 Hz), 10.94 (1H, s). Synthesis Example 42b N- (8-Chloroquinoline-3-yl) -2, 3-dihydro-5-benzofuranosulfonamide 57 mg of the title compound was obtained using 30 mg (0.17 mmol, Produssion Example 9b) of 3- amino-8-sloroginoline and 44 mg (0.20 mmol) of 5-slorosulfonyl-2, 3-dihydrobenzofuran in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 3.19 (2H, t, J = 8.8 Hz), 4.58 (2H, t, J = 8.8 Hz), 6.86 (1H , d, J = 8.8 Hz), 7.23 (1H, t, J = 7.6 Hz), 7.62 (1H, dd, J = 1.6, 8.8 Hz), 7.72 (1H, d, J = 1.6 Hz), "7.80 (1H, d, J = 7.6 Hz), 7.92 (1H, d, J = 7.6 Hz), 8.03 ( 1 HOUR, d, J = 2.4 Hz), 8.73 (1H, d, J = 2.4 Hz), 10.85 (1H, s). Synthesis Example 43b N- (8-Chloro-4-vinylguinoline-3-yl) -4-siabensenosulfonamide 15 mg of the title compound was obtained using 30 mg (0.15 mmol, Produssion Example 12b) of 3-amino acid 4-vinyl-8-sorogoginoline and 36 mg (0.18 mmol) of 4-siabensenosulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 5.29 (1H, d, J = 17.6 Hz), 5.59 (1H, d, J = 11.6 Hz), 6.75 (1H , dd, J = 11.6, 17.6 Hz), 7.59 (1H, t, J = 8.0 Hz), 7.80 (2H, dd, J = 8.8 Hz), 7.96 (1H, d, J = 8.0 Hz), 8.00-8.04 (3H, m), 8.74 (1H, s), 10.58 (1H, s). Exemplary Synthesis 44b N- (8-Trifluoro-ethyl-quinoline-3-yl) -5- (N-asethyl-indoline) sulfonamide 186 mg of the title compound were obtained using 109 mg (0.51 mmol, Produssion Example 10b) of 3-amino -8-trifluoromethylguinoline and 200 mg (0.77 mmol) of 5-slorosulfonyl-N-asetilindoline in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.13 (3H, s), 3.14 (2H, t, J = 8.0 Hz), 4.09 (2H, t, J = 8, 8 Hz), 7.67 (1H, t, J = 8.4 Hz), 7.69-7.73 (2H, m), 8.01 (1H, d, J = 7.2 Hz), 8 , 07-8.09 (2H, ra), 8.24 (1H, d, J = 8.4 Hz), 8.73 (1H, d, J = 2.8 Hz), 10.98 (1H, S). Synthesis Example 45b N- (8-Bromoguinoline-3-yl) -2-methylthio-5-pyridinesulfonamide 197 mg (0.556 mmol) of green crystals were obtained using 100 mg (0.56 mmol, Production Example 5b) of 3 -amino-8-bromoguinoline and 142 mg (0.67 mmol) of 2-sloro-5-pyridinesulfonyl chloride in the same manner as in Synthesis Example lb. Dimethylformamide (1 ml), pyridine (1 ml) and 111 mg (1.6 mmol) of sodium thiomethoxide were added to 60 mg (0.17 mmol) of the crystals, followed by stirring at room temperature for 3 hours. Brine was added to the rejection solution, followed by an addition with ethyl acetate. The organic layer was sessed over magnesium sulfate and sonsented to give a residue. The residue was purified by silica gel chromatography to give 62 mg of the title compound. XH-NMR (DMSO-de) d (ppm): 3.33 (3H, s), 7.47 (1H, d, J = 8.8 Hz), 7.55 (1H, t, J = 8.0 Hz), 7.84 (1H, d, J = 6.8 Hz), 1, 97 (1H, d, J = 8.8 Hz), 7.98 (1H, d, J = 8.8 Hz), 8.13 (1H, d, J = 2.0 Hz), 8.74 (1H, d, J = 2.4 Hz), 8.82 (1H, d, J = 2.0 Hz), 11.16 (1H, s). Synthesis Example 46b N- (8-Bromoquinoline-3-yl) -4- (2-methy1sulfoni1eti1) bensenosulfonamide 55 mg of the title compound was obtained using 30 mg (0.13 mmol, Produssion Example 5b) of 3-amino -8-bromoquinoline and 57 rag (0.20 mmol) of 4- (2-methylsulfonylethyl) bensenosulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.92 (3H, s), 3.00-3.05 (2H, m), 3.37-3.44 (2H, m), 7, 46 (1H, t, J = 7.6 Hz), 7.48 (2H, d, J = 8.0 Hz), 7.80 (2H, d, J = 8.0 Hz), 7.96 ( 1H, d, J = 7.6 Hz), 7.99 (1H, d, J = 7.6 Hz), 8.04 (1H, d, J = 2.4 Hz), 8.71 (1H, d, J = 2.4 Hz), 11.02 (1H, s) Synthesis Example 47b N- (8-Bromoquinoline-3-yl) -4-oxa-7-benzothiosromanosulfonamide 99 mg of the title compound was obtained using 51 mg (0.23 mmol, Produssion Example 5b) of 3-amino-8-bromoquinoline and 86 mg (0.34 mmol) of 7-slorosulfonyl-4-oxa-benzothiosroman in the same manner as in the Synthesis Example lb. XH-NMR (DMSO-ds) d (ppm): 3.18 (2H, t, J = 8.4 Hz), 4.39 (2H, t, J = 8.4 Hz), 6.92 (1H , d, J = 8.8 Hz), 7.42 (1H, dd, J = 2.4, 8.8 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.59 (1H, d, J = 2.4 Hz), 7.99 (1H, d, J = 7.6 Hz), 8.02 (1H, d, J = 7.6 Hz), 8.05 (1H , ansha), 8.71 (1H, d, J = 2.4 Hz), 10.92 (1H, s). i li i iiii Miiii pir i.? ^^ *. ~? ^ t ~ ^? A ^ »M ~ * ^. 3? A Synthesis Example 48b N- (8-Bromoquinoline-3-yl) -4- (2-asetamidoethyl) bensenosulfonamide 56 mg of the title compound was obtained using 30 mg (0.13 mmol, Production Example 5b) of 3-amino-8-bromoquinoline and 201 mg (0.77 mmol) of N- (4-chlorosulfonyl-phenethylethyl) asetamide in the same manner as in Example Synthesis lb. XH-NMR (DMSO-ds) d (ppm): 2.71 (2H, t, J = 7.2 Hz), 3.25-3.20 (2H, m), 7.37 (2H, d, J = 8.4 Hz), 7.46 (1H, t, J = 8.0 Hz), 7.78 (2H, d, J = 8.4 Hz), 7.86 (1H, ansha), 7 , 97 (1H, d, J = 8.0 Hz), 8.00 (1H, d, J = 8.0 Hz), 8.04 (1H, d, J = 2.8 Hz), 8.72 (1H, d, J = 2.8 Hz), 10.99 (1H, s). Synthesis Example 49b N- (8-Bromoquinoline-3-yl) -1, 2, 3, 4-tetrahydro-N-asethyl-7-isoquinolinesulfonamide 180 mg of green crystals were obtained using 145 rag (0.65 mmol, Produssion Example 5b) of 3-amino-8-bromoquinoline and 277 mg (0.85 mmol) of 1,2,3,4-tetrahydro-2- (trifluorophenyl) isoginoline-7- sluride sulfonyl in the same manner as in Synthesis Example lb. Ethanol (20 ml) and a 1 N sodium hydroxide solution (0.5 ml) were added to the crystals, followed by stirring at room temperature for 30 minutes. An asymmetric dissolution of 1 N of a very fine slurry-dichloride (0.4 ml) was adhered to the reassuming solution, followed by extrasysis are ethyl acetate. The sapa organelle was washed, brine, blended on magnesium sulfate and filtered, to give a residue. Pyridine (0.5 ml) and anhydrous asystid acid (0.014 ml) were added to the residue, followed by stirring at room temperature for one hour. Brine was added, followed by extraction with ethyl acetate. The organic layer was sessed over magnesium sulfate and filtered. Then, the residue was purified by chromatography on silica gel, to give 113 mg of the title substance. XH-NMR (DMSO-de) d (ppm): 1.19-1.28 (2H, m), 2.05 (3H, s), I ^ AA * *. **** ^^ li t | zstÜ f'.l? - '... ^^ M .. ^,., »Faith .... -,., ^ T? U? Mátm? Lt máM *? M *? *? m * ^ 2.97 (1H, t, J = 6.4 Hz), 3.03 (1H, t, J = 6.4 Hz), 3.75 (1H, t, J = 6.4 Hz) , 4.73 (1H, s), 7.37 (1H, t, J = 8.8 Hz), 7.53-7.58 (1H, m), 7.75-7.87 (2H, m ), 7.91 (1H, d, J = 8.0 Hz), 8.19-8.27 (2H, m), 8.76-8.78 (1H, m). Synthesis Example 50b N- (8-Broraoguinoline-3-yl) -1, 1-dioxido-6-benzothiosromanosulfonamide Blistered crystals were obtained using 71 mg (0.32 mmol, Produssion Example 5b) of 3-amino-8- bromoguinoline and 119 mg (0.48 mmol) of 6-slorosulfonylbenzothiosroman. Under cooling are ice, sloroform (10 ml) and methyloperbenzoiso (145 mg) were added to the glazings under cooling are ice, followed by agitation at room temperature for one hour. A saturated aqueous solution of sodium thiosulfate was added, followed by an addition with ethyl acetate. The sapa organelle was washed and brined over magnesium sulfate. After sonsentration, the residue was purified by silica gel chromatography to give 113 mg of the title substance. XH-NMR (DMS0-d6) d (ppm): 2.26-2.29 (2H, m), 3.05 (2H, t, J = 6.0 Hz), 3.53-3.56 ( 2H, m), 7.48 (1H, t, J = 7.6 Hz), 7.86-7.90 (2H, m), 7.96-8.04 (3H, m), 8.10 (1H, d, J = 2.4 Hz), 8.75 (1H, d, J = 2.4 Hz), 11.24 (1H, s). Synthesis Example 51b N- (8-Broraoguinoline-3-yl) -4- (3-methy1sulfonylpropi1) bensenosulfonamide 62 mg of the title compound was obtained using 33 mg (0.14 mmol, Produssion Example 5b) of 3-arnino -8- bromoguinoline and 66 mg (0.22 mmol) of 4- (3-methylsulfonylpropyl) bensenosulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 1.90-1.98 (2H, m), 2.72 (2H, t, J = 8.0 Hz), 2.93 (3H, s) , 3.06 (2H, t, J = 8.0 Hz), 7.42 (2H, d, J = 8.0 Hz), 7.46 (1H, d, J = 7.6 Hz), 7 , 97 (2H, d, J = 7.6 Hz), 8.00 (1H, d, J = 7.6 Hz), 8.05 (1H, d, J = 2.4 Hz), 8.72 (1H, d, J = 2.4 Hz), 11.01 (1H, s).
Synthesis Example 52b N- (8-Bromoguinoline-3-yl) -4-fluoro-bensenosulfonamide 50 mg of the title compound was obtained using 33 mg (0.14 mmol, Produssion Example 5b) of 3-amino-8- bromoguinoline and 39 mg (0.20 mmol) of 4-fluorobenzenesulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.40 (1H, t, J = 8.8 Hz), 7.47 (1H, t, J = 7.6 Hz), 7.89-7 , 93 (2H, m), 9.78 (1H, dd, J = 0.9, 7.6 Hz), 8.01 (1H, dd, J = 0.9, 7.6 Hz), 8, 06 (1H, d, J = 2.4 Hz), 8.71 (1H, d, J = 2.4 Hz), 11.06 (1H, s). Synthesis Example 53b N- (8 -Bromoguinoline-3-yl) -4-methoxy-2-pyridazinesulfonamide Under cooling are ice, slurry gas was bubbled in a dissolution of solid slurry-dried (8 ml) containing 0.86 g (3 , 7 mmol, Produssion Example 14b) of 2-bentylthio-5-methoxypyridazine for one hour, followed by agitation. Then, water-ice was added to the solder of reassess, followed by extrasion, ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and filtered to give 700 mg (2.1 mmol) of a residue. 93 mg of the title compound were obtained using 180 mg (0.54 mmol) of the residue and 60 mg (0.27 mmol, Produssion Example 5b) of 3-amino-8-bromoguinoline in the same manner as in Example Synthesis lb. XH-NMR (DMSO-de) d (ppm): 4.07 (3H, s), 7.44 (1H, d, J = 9.2 Hz), 7.47 (1H, t, J = 7, 6 Hz), 7.96 (1H, t, J = 7.6 Hz), 8.02 (1H, t, J = 7.6 Hz), 8.13 (1H, d, J = 2.4 Hz ), 8.17 (1H, d, J = 9.2 Hz), 8.82 (1H, d, J = 2.4 Hz), 11.54 (1H, s). Synthesis Example 54b N- (8-Bromoguinoline-3-yl) -bensenosulfonamide 49 mg of the title compound was obtained using 30 mg (0.13 mmol, Produssion Example 5b) of 3-amino-8- bromoguinoline and 35 rag (0.20 mmol) of bensenosulfonyl sloride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.45 (1H, d, J = 7.6 Hz), 7.53-7.63 (3H, m), 7.84-7.86 ( 2H, m), 7.96 (1H, dd, J = 1.2, 7.6 Hz), 7.99 (1H, dd, J = 1.2, 7.6 Hz), 8.04 (1H , d, J = 2.8 Hz), 8.71 (1H, d, J = 2.8 Hz), 11.02 (1H, s). Synthesis Example 55b N- (8-Bromoquinoline-3-yl) -4-carbo-xyamido-2-pyridinesulfonamide. Sloroidal gas was bubbled in a dissolution of solid chlorhydric dichloride (16 ml) containing 1.1 g (4, 3 mpjol, Produssion Example 15b) of 2-bhenylthio-4-carbo-xyamidopyridine for one hour under cooling are ice, followed by agitation. Then, the reassessment solution was adhered to ice water, followed by extrassion are ethyl acetate. The sapa organelia was washed with water and brine, dried over magnesium sulfate and filtered. 37 mg of the title compound was obtained using 140 mg (0.40 mmol) of a residue and 45 mg (0.20 mmol) of 3-amino-8-bromo-guinoline in the same manner as in the Synthesis-lb Example . XH-NMR (DMSO-de) d (ppm): 7.46 (1H, d, J = 8.0 Hz), 7.94-7.96 (2H, m), 8.00-8.02 ( 2H, m), 8.12 (1H, d, J = 2.4 Hz), 8.44 (1H, ansha), 8.49 (1H, ansha), 8.83-8.85 (2H, m ), 11.35 (1H, s) Synthesis Example 56b N- (8-Bromoguinoline-3-yl) -3-rae-toxibensenosulfonamide 70 mg of the title compound was obtained using 40 mg (0.18 mmol, Example Produssion 5b) of 3-amino-8-bromoguinoline and 56 mg (0.27 mmol) of 3-methoxybenzenesulfonyl sluride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 3.76 (3H, s), 7.17 (1H, dd, J = 2.8, 8.0 Hz), 7.34-7.40 ( 2H, m), 7.45 (1H, t, J = 7.6 Hz), 7.46 (1H, t, J = 7.6 Hz), 7.99 (2H, t, J = 7.6 Hz), 8.07 (1H, d, J = 2.4 Hz), 8.72 (2H, m), 11.35 (1H, d, J = 2.4 Hz) Synthesis Example 57b - -W - (8-Bromoguinoline-3-yl) -3-hydroxybenzenesulfonamide 73 mg of the title compound were obtained using 45 mg (0.20 mmol, Produssion Example 5b) of 3-amino-8-bromoguinoline and 117 mg ( 0.61 mmol) of 3-hydroxybenzenesulfonyl sloride in the same manner as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 6.97 (1H, d, J = 8.0 Hz), 7.18 (1H, ansha), 7.25 (1H, d, J = 8.0 Hz), 7.34 (1H, t, J = 8.0 Hz), 7.47 (1H, t, J = 8.0 Hz), 7.97 (1H, d, J = 8.0 Hz), 8.01 (1H, d, J = 8.0 Hz), 8.04 (1H, d, J = 2.4 Hz), 8.73 (1H, d, J = 2.4 Hz), 10.15 (1H, s), 10.96 (1H, s). Synthesis Example 58b N- (4-Bromoguinoline-7-yl) -4-chloro-robensenosulfonamide 20 mg (0.09 mmol, Produssion Example 20b) of 7-amino-4-bromoisoguinoline were dissolved in 1.5 ml of pyridine, to which 23 mg of sloroide of 4-slorobensenosulfonyl were adhered, followed by agitation at room temperature during noshe. Water was added to the reassumption solution, and the mixture was extracted as ethyl acetate. The extra was blended on magnesium sulfate and filtered. Then, the resulting residue was purified by chromatography in a thin layer of silica gel, to give 13 mg of the title substance. Melting point: gradual deposition from 229 ° C. XH-NMR (DMSO-de) d (ppm): 7.59-7.61 (2H, m), 7.66 (1H, dd, J = 2 Hz, 9.2 Hz), 7.82-7 , 84 (3H, m), 7.99 (1H, d, J = 9.2 Hz), 8.60 (1H, s). Synthesis Example 59b N- (4-Bromoisoguinoline-7-yl) -6-chloro-3-pyridinesulfonamide The title compound was obtained using 7-amino-4-isoguinoline (Produssion Example 20b) and 6-sloroidal slurry. 3-pyridinesulfonyl in the same manner as in the Example Peep of Synthesis 57b. X H-NMR (DMSO-de) d (ppm): 7.66 (1 H, dd, J = 2.4 Hz, 9.2 Hz), 7.70 (1 H, d, J = 8.4 Hz), 7.89 (1H, d, J = 2.4 Hz), 8.02 (1H, d, J = 9.2 Hz), 8.20 (1H, dd, J = 2.4 Hz, 8.4 Hz), 8.64 (IB, s), 8.84 (1H, d, J = 2.4 Hz), 9.26 (1H, s). Synthesis Example 60b 2- (4-Chlorobenzenesulfonylaraine) -1,6-naphthyridine 2-Amino-1,6-naphthyridine (200 mg, Production Example 25b) was dissolved in dichloromethane (6.0 ml). Then triethylamine (0.20 ml) and 4-slorobensenosulfonyl slurry (0.31 g) were added, followed by stirring at 40 ° C for 1.5 hours. A saturated dissolution of saturated sodium bisarbonate was adhered to, followed by extrasysis are ethyl acetate. The extra was washed is brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel solnum, to give the title compound (84 mg, 21.44%) yellow silica gel. XH-NMR (CDC13) d (ppm): 7.10 (1H, d, J = 9.2 Hz), 7.37 (1H, d, J = 5.4 Hz), 7.46 (2H, d , J = 8.8 Hz), 7.93 (2H, d, J = 8.8 Hz), 8.94 (1H, d, J = 9.2 Hz), 8.66 (1H, d, J = 5.4 Hz), 8.92 (1H, s ansho). Synthesis Example 61b l-Chloro-6- (4-siabensenosulfonyl-amino) isoguinoline The title compound was obtained using 6-amino-1-sloro-isoguinoline (Produssion Example 23b) and 4-Silobensenosulfonyl Sluride are the same method In Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 7.52 (1H, dd, J = 2.0, 8.8 Hz), 7.68 (1H, d, J = 2.0 Hz), 7 , 79 (1H, d, J = 5.6 Hz), 8.03 (4H, m), 8.18 (1H, d, J = 5.6 Hz), 8.21 (1H, d, J = 8.8 Hz), 11.36 (1H, s). Synthesis Example 62b l-Chloro-6- (4-sulfobensenosulfonylamino) isoguinoline The title compound was obtained using 6-amino-1-sloro-isoquinoline (Produssion Example 23b) and 4-slorobensenosulfonyl slurry are the same method as in the Synthetic Formula lb. XH-NMR (CDC13) d (ppm): 7.33 (1H, s ansho), 7.39 (1H, dd, J = 2.0, 8.8 Hz), 7.44 (2H, d, J = 8.8 Hz), 7.50 (1H, d, J = 5.6 Hz), 7.58 (1H, d, J = 2.0 Hz), 7.81 (2H, d, J = 8 , 8 Hz), 8.24 (1H, d, J = 5.6 Hz), 8.25 (1H, d, J = 8.8 Hz). FAB-MS: 353. Synthesis Example 63b l-Chloro-6- (4-pyrrolidin-l-ylsul-fonyl) bensenosulfonylamino) isoquinoline Obtained the subject substance using 6-amino-1-sloro-isoquinoline (Produssion Example 23b ) and sluride of 4- (pyrrolidin-1-ylsulfonyl) bensenosulfonyl are the same method as in Synthesis Example lb. XH-NMR (CDCl3) d (ppm): 1.71 (4H, m), 3.20 (4H, t, J = 7.0 Hz), 7.46 (1H, d, J = 5.4 Hz) ), 7.49 (1H, dd, J = 2.0, 9.2 Hz), 7.61 (1H, d, J = 2.0 Hz), 7.87 (2H, d, J = 8, 8 Hz), 8.02 (2H, d, J = 8.8 Hz), 8.19 (1H, d, J = 9.2 Hz), 8.20 (1H, d, J = 5.4 Hz ), 9.72 (1H, s). Synthesis Example 64b l-Chloro-6- (4- (N-ethylsulfaraoyl) bensenosulfonylamino) isoquinoline The title compound was obtained using 6-amino-1-sloro-isoquinoline (Produssion Example 23b) and slurry of 4- (N -ethylsulfamoyl) bensenosulfonyl are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 0.81 (3H, t, J = 7.2 Hz), 2.73 (2H, m), 7.53 (1H, d, J = 9, 2 Hz), 7.67 (1H, s), 7.75 (1H, d, J = 6.0 Hz), 7.78 (1H, d, J = 6.0 Hz), 7.92 (2H , d, J .- = 8.0 Hz). Synthesis Example 65b l-Methoxy-6- (pyridine-3-ylsulfonyl-amino) isoquinoline The title compound was obtained using 6-amino-1-methoxyisoquinoline (Produssion Example 43b) and 3-pyridinesulfonyl sluride are the same method that in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm) | 4.09 (3H, s), 7.09 (1H, d, J = 6.0 Hz), 7.25 (1H, dd, J = 2.0, 8.8 Hz), 7.37 (1H , d, J = 8.0, 8.8 Hz), 7.48 (1H, d, J = 2.0 Hz), 7.96 (1H, d, J = 6.0 Hz), 8.07 (1H, ddd, J = 1.6, 2.0, 8.0 Hz), 8.14 (1H, d, J = 8.8 Hz), 8.74 (1H, dd, J = 1.6 , 8.8 Hz), 9.08 (1H, d, J = 2.0 Hz). ESI-MS: 316.0. Synthesis Example 66b 6- (4-Cyanobensenosulfonylamino) -1-methoxyisoquinoline The title compound was obtained using 6-amino-1-methoxyisoquinoline (Produssion Example 43b) and 4 -silybensenosulfonyl sluride are the same method as in the Synthesis lb. X H-NMR (DMSO-de) d (ppm): 3, 97 (3H, s), 7.25 (1H, d, J = 5.6 Hz), 7.32 (1H, d, J = 8.8 Hz), 7.51 (1H, s), 7 , 90 (1H, d, J = 5.6 Hz), 7.97 (2H, d, J = 7.6 Hz), 8.01 (2H, d, J = 7.6 Hz), 8.03 (1H, d, J = 8.8 Hz). Synthesis Example 67b 6- (4-Carbamoylbensenosulfonylamino) -1-methoxyisoquinoline The title compound was obtained using 6- (4-siabensenosulfonylamino) -1-methoxyisoquinoline (Produssion Example 65b) according to the method described in Synthesis, 949 ( 1989). XH-NMR (DMSO-de) d (ppm): 3.96 (3H, s), 7.24 (1H, d, J = 6.4 Hz), 7.33 (1H, d, J = 9, 2 Hz), 7.51 (1H, s), 7.55 (1H, s ansho), 7.88 (1H, d, J = 6.4 Hz), 7.89 (2H, d, J = 8 , 0 Hz), 7.93 (2H, d, J = 8.0 Hz), 8.01 (1H, d, J = 9.2 Hz), 8.06 (1H, s ansho), 10.95 (1H, s). FAB-MS: 358. Synthesis Example 68b 6- (4- (N-Ethylsulfaraoyl) bensenosulphonylamino) -1-methoxyisoquinoline The title compound was obtained using 6-amino-1-methoxyisoquinoline (Produssion Example 43b) and slurry from 4- (N-ethylsulfamoyl) bensenosulfonyl are the same method as in Synthesis Example lb. XH-NMR (DMSO-ds) d (ppm): 0.81 (3H, t, J = 6.8 Hz), 2.71 (2H, m), 3.96 (3H, s), 7.23 (1H, d, J = 6.4 Hz), 7.32 (1H, d, J- 8.8 Hz), 7.48 (1H, s), 7.73 (1H, s ansho), 7, 89 (2H, d, J = 8.0 Hz), 7.90 (1H, d, J = 6.4 Hz), 8.01 (3H, m), 11.03 (1H, s ansho). ESI MS: 422.0. Synthesis Example 69b 6- (2-Aminopyridine-5-ylsulfonylamine) -1-methoxyisoguinoline The title compound was obtained using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and 6-amino-3-slurry pyridinesulfonyl are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 3.96 (3H, s), 6.39 (1H, d, J = 8.8 Hz), 6.89 (2H, s), 7.25 (1H, d, J = 4.2 Hz), 7.32 (1H, d, J = 9.2 Hz), 7.47 (1H, s), 7.64 (1H, d, J = 9, 2 Hz), 7.89 (1H, d, J = 4.2 Hz), 8.01 (1H, d, J = 8.8 Hz), 8.31 (1H, s), 10.95 (1H , s). ESI MS: 331.0. Synthesis Example 70b l-Methoxy-6- (4-methylbensenosulphonylamino) isoguinoline The title compound was obtained using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and 4-toluenesulfonyl sluride are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.28 (3H, s), 3.96 (3H, s), 7.22 (1H, d, J = 6.0 Hz), 7.32 (3H, m), 7.48 (1H, s), 7.71 (2H, d, J = 8.4 Hz), 7.88 (1H, d, J = 6.0 Hz), 8.00 (1H, d, J = 9.2 Hz), 10.79 (1H, s). ESI MS: 329.0. Synthesis Example 71b 6- (4-Asethylaminobensenosulfonylamino) -1-methoxyisoguinoline The title compound was obtained using 6-amino-1 Methodisoguinoline (Produssion Example 43b) and sluride of 4 -asetamidobensenosulfonyl are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.01 (3H, s), 3.96 (3H, s), 7.23 (1H, d, J = 6.0 Hz), 7.32 (1H, d, J = 9.2 Hz), 7.47 (1H, s), 7.67 (2H, d, J = 8.8 Hz), 7.76 (2H, d, J = 8, 8 Hz). 7.88 (1H, d, J = 6.0 Hz), 8.00 (1H, d, J = 9.2 Hz), 10.26 (1H, s), 10.75 (1H, s). ESI MS: 372.1. Synthesis Example 72b 6- (4-Methanesulfonylaminobensenosul-fonilamino) -1-raetoxiisoguinoline The somatose synthesized using 6-amino-1-methoxy-isoguinoline (Produssion Example 43b) and 4-nitrobensenosulfonyl sluride in the same manner as in Example of Synthesis lb was reproduced in the same manner as in Produssion Example 170b, to reduce the nitro group thereof. The resulting suspension was dissolved in pyridine and was charged with methanesulfonyl slurry under cooling are ice, followed by agitation for 4 hours as it was. It was added brine, followed by extrassion are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel solnum and the resulting crystals were recrystallized from ethanol, to give the title co-position. XH-NMR (DMSO-de) d (ppm): 3.06 (3H, s), 3.97 (3H, s), 7.24 (3H, m), 7.33 (1H, d, J = 9.0 Hz), 7.49 (1H, s), 7.79 (2H, d, J = 8.8 Hz), 7.89 (1H, d, J = 6.0 Hz), 8.01 (1H, d, J = 9.0 Hz), 10.39 (1H, s), 10.80 (1H, s). ESI MS: 372.1. Synthesis Example 73b 6- (2-Chloropyridine-5-ylsulfonyl-amino) -1-methoxyisoguinoline The title compound was obtained using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and slurry of ....... A -...-. A.,. - ^ ^ ^ ^ ^ ^ ^ ^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 6-sloro-3-pyridinesulfonyl are the same method as in the Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 3.31 (3H, s), 3.99 (3H, s), 7.30 (1H, d, J = 6.0 Hz), 7.34 (1H, d, J = 8.8 Hz), 7.56 (1H, s), 7.71 (1H, d, J = 8, 8 Hz), 7.92 (1H, d, J = 6.0 Hz), 8.06 (1H, d, J = 8.8 Hz), 8.19 (1H, d, J = 8.8 Hz ), 11.13 (1H, s). ESI MS: 350.1. Synthesis Example 74b l-Methoxy-6- (3-phenyl-bensenosulfo-nylamino) isoguinoline The title compound was obtained using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and slurry of 3 - . 3-Toluenesulfonyl are the same method as in Example Synthesis lb. XH-NMR (DMSO-de) d (ppm): 2.31 (3H, s), 3.96 (3H, s), 7.22 (1H, d, J = 6.0 Hz), 7.32 (1H, dd, J = 2.0, 8.8 Hz), 7.39 (2H, m), 7.47 (1H, d, J = 2.0 Hz), 7.62 (1H, m) 7.67 (1H, s), 7.87 (1H, d, J = 6.0 Hz), 8.00 (1H, d, J = 8.8 Hz), 10.84 (1H, s).
Synthesis Example 75b 6-Bensylsulfonylamino-l-methoxy-isoguinoline The title compound was ined using 6-amino-l-methoxyisoguinoline (Produssion Example 43b) and bensylsulfonyl slurry are the same method as in Synthesis Example lb. XH-NMR (CDC13) d (ppm): 4.13 (3H, s), 4.42 (2H, s), 6.69 (1H, s ansho), 7.13 (2H, m), 7, 22 (2H, m), 7.30-7.37 (3H, m), 7.50 (1H, d, J = 2.4 Hz), 7.99 (1H, d, J = 6.0 Hz), 8.20 (1H, d, J = 8.8 Hz). Synthesis Example 76b 6- (3-Cyanobensenosulfonylamino) -1-methoxyisoguinoline The title compound was ined using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and slurry of 3 - . 3-Sianobensenosulfonyl is the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 3.98 (3H, s), 7.28 (1H, d, J = 6.0) ^ & , it.á.á, ifciá¿A. .. ^^ Hz), 7.34 (1H, dd, J = 2.0, 8.8 Hz), 7.53 (1H, d, J = 2.0 Hz), 7.75 (1H, dd , J = 8.0, 8.0 Hz), 7.91 (1H, d, J = 6.0 Hz), 8.01 (1H, d, J = 8.8 Hz), 8.09 (2H , m), 9.29 (1H, m), 11.05 (1H, s). Synthesis Example 77b l-Methoxy-6- (4-thiazol-2-ylbenseno-sulfonylamino) isoguinoline The somatose (40 mg) ined using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and sodium slurry was refluxed at reflux. 4-Iodobensenosulfonyl are the same method as in Synthesis Example lb, 2-tri-n-butylstannylthiazole (136 mg) and tetrakis (triphenyl-phosphine) palladium (0) (11 mg) for one hour in toluene under nitrogen . After evaporating the solvent, the residue was purified by silica gel solnum The resulting crystals were recrystallized from methanol to give the title suspension (20 mg) XH-NMR (CDC13) d (ppm) : 4.08 (3H, s), 6.94 (1H, S ansho), 7.09 (1H, d, J = 6.0 Hz), 7.23 (1H, dd, J = 2.0, 8.8 Hz), 7.41 (1H, d, J = 3.6 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.89 (2H, d, J = 8, 4 Hz), 7.90 (1H, d, J = 8.6 Hz), 7.95 (1H, d, J = 6.0 Hz), 7 82 (2H, d, J = 8.4 Hz) , 8.13 (1H, d, J = 8.8 Hz) Synthesis Example 78b 6- (4-chlorobensenosulfonylamino) -1-methoxyisoguinoline The title compound was ined using 6-amino-1-methoxyisoguinoline (Produssion Example 43b) and 4-slorobensenosulfonyl sluride are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 4.00 (3H, s), 7.27 (1H, d, J = 5.6 Hz), 7.45 (1H, dd, J = 2.0, 8.8 Hz), 7.53 (1H, d, J = 2.0 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.85 (1H, d, J = 8.8 Hz), 7.92 (1H, d, J = 5.6 Hz), 8.06, (1H, J = 8.8 Hz), 10.97 (1H, s).
Synthesis Example 79b 6- (4-Chlorobensenosulfonylamino) -1-methylisoquinoline The title compound was ined using 6-amino-1-methylisoquinoline (Produssion Example 33b) and slurry 4- liiieiieiieeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeeee 1 ii 11"^" ^ "" "^^" "^ IIMltlM slorobensenosulfonyl are the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 2.76 (3H, s) , 7.56 (1H, d, J = 6.0 Hz), 7.52 (2H, m), 7.60 (2H, d, J = 8.8 Hz), 7.82 (2H, d, J - 8.8 Hz), 8.08 (1H, d, J = 9.2 Hz), 8.20 (1H, d, J = 6.0 Hz) ESI-MS: 333.0. Synthesis 80b 6- (4-Chlorobensenosulfonilaraine) -1-ethylisoquinoline The title compound was ined using 6-amino-1-ethyl isoquinoline (Produssion Example 48b) and 4-slorobensenosulfonyl slurry in the same manner as in Synthesis Example lb XH-NMR (DMSO-de) d (ppm): 1.39 (3H, t, J = 7.6 Hz), 3.25 (2H, s, J = 7.6 Hz), 7.35 ( 1H, dd, J = 2.4, 9.2 Hz), 7.38 (1H, d, J = 5.6 Hz), 7.41 (2H, d, J = 8.8 Hz), 7, 53 (1H, d, J = 2.4 Hz), 7.81 (2H, d, J = 8.8 Hz), 8.05 (1H, d, J = 9.2 Hz), 8.37 ( 1H, d, J = 5.6 Hz) ESI-MS: 347.0 Synthesis Example 81b 6- (4-Chlorobensenosulfonylamino) -4-ethylisoquinoline The title compound was ined. The use of 6-amino-4-ethylisoquinoline (Produssion Example 66b) and 4-slorobensenosulfonyl slurry is the same method as in Synthesis Example lb. XH-NMR (DMSO-de) d (ppm): 1, 18 (3H, t, J = 7.2 Hz), 2.85 (2H, s, J = 7.2 Hz), 7.38 (1H, d, J = 8.8 Hz), 7.60 (1H, s), 7.62 (2H, d, J = 8.0 Hz), 7.82 (2H, d, J = 8.0 Hz), 8.00 (1H, d, J = 8, 8 Hz), 8.26 (1H, s), 8.99 (1H, s). Synthesis Example 82b 6- (4-Chlorobensenosulfonylamino) -4-methylisoquinoline The title compound was obtained using 6-amino-4-methylisoquinoline (Produssion Example 58b) and 4-slorobensenosulfonyl slurry are the same method as in Example Synthesis lb.
XH-NMR (DMSO-dg) d (ppm): 2.43 (3H, s), 7.41 (1H, d, J = 8.8 Hz), 7.56 (1H, s), 7.62. (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.99 (1H, d, J = 8.8 Hz), 8.26 (1H , s), 8.98 (1H, s), 11.09 (1H, s ansho). Synthesis Example 83b 6- (4-Chlorobensenosulfonylamino) -3-methylisoquinoline The title compound was obtained using 6-amino-3-methylisoquinoline (Produssion Example 76b) and 4-slorobensenosulfonyl slurry are the same method as in Example Synthesis lb. XH-NMR (DMSO-de) d (ppm): 2.53 (3H, s), 7.30 (1H, d, J = 8.8 Hz), 7.45 (1H, s), 7.50 (1H, s), 7.62 (2H, d, J = 8.4 Hz), 7.84 (2H, d, J = 8.4 Hz), 7.93 (1H, d, J = 8, 8 Hz), 9.03 (1H, s). Synthesis Example 84b 6- (4-Chlorobensenosulfonilaraine) -1- sissisoquinoline The somatum obtained was dissolved using 6-aminoisoquinoline (0.5 g, Synthesis, 733 (1975)) and 4-sulfosenosulfonyl sluride (0.88 g) are the same method as in Synthesis Example lb in sloroform (150 ml). It was adhered to, under cooling, ice, m-sloroperbenzoiso (0.9 g), followed by agitation at room temperature during noshe. The solvent was evaporated, and the resulting crystals were washed diethyl ether, reslurried by filtration and bent, to give 6- (4-sulfosenosulfonylamino) -isoquinoline-N-oxide (1.072 g). 50 mg of the prodrug was dissolved in asetonitrile (1.5 ml), to which was added trimethyl silyne (0.08 ml) and triethylamine (0.04 ml), followed by refluxing for 3.5 hours. After evaporating the solvent, the residue was purified by silica gel column, to give the title compound (23 mg, 64%) yellow crystals. XH-NMR (DMSO-de) d (ppm): 7.66 (2H, d, J = 8, 8 Hz), 7.67 (1H, dd, J = 2, 0, 9, 2 Hz), 7 , 80 (1H, d, J = 2.0 Hz), 7, 93 (2H, d, J = 8.8 Hz), 8.17 (1H, d, J = 9.2 Hz), 8.18 (1H, d, J = 5, 6 Hz), 8.59 (1H, d, J = 5.6 Hz). ESI-MS: 344.1 Synthesis Example 85b l-Carbamoyl-6- (4-slorobenseno-sulfonylamino) isoquinoline The crystals obtained from 6- (4-slorobenzenesulfonylamino) -1-sianoisoquinoline (30 mg, Example Synthesis 83b) of agreement are the method dessrito in Synthesis, 949 (1989) were washed diethyl ether, to give the compound of the title (26 mg, 82%) somo sristales insoloros. XH-NMR (CDC13) d (ppm): 6.25 (1H, s ansho), 7.35 (2H, d, J = 8.8 Hz), 7.43 (1H, dd, J = 2.0 , 9.2 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.66 (1H, d, J = 6.8 Hz), 7.81 (2H, d, J = 8 , 8 Hz), 8.04 (1H, s ansho), 8.37 (1H, s ansho), 9.32 (1H, d, J = 9.2 Hz), 9.76 (1H, s ansho) . Synthesis Example 86b 6- (4-Chlorobensenosulfonylamino) -1-methylaminoisoquinoline L-sloro-6- (4-sulfobensenosulfonylamino) isoquinoline (50 mg, Synthesis Example 61b) and a 40% methanolamine methylamine disulphide ( 5.0 ml) at 130 ° C in a serrated tube for 18 hours. After cooling, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel solnum, to give the title compound (28 mg, 52%) as a yellow-colored solid. X H-NMR (CDCl 3) d (ppm): 3.14 (3 H, s), 5.22 (1 H, s ansho), 6.89 (1 H, d, J = 6.0 Hz), 7.19 ( 1H, dd, J = 2.4 Hz, 9.2 Hz), 7.31 (1H, d, J = 2.4 Hz), 7.40 (2H, d, J = 8.8 Hz), 7 , 64 (1H, d, J = 9.2 Hz), 7.73 (2H, d, J = 8.8 Hz), 7.98 (1H, d, J = 6.0 Hz). Synthesis Example 87b 1-Amino-6- (4-sulfosenosulfo- nilaraine) isoquinoline The crystals obtained using 6- (4-slorobensenosulphonylamino) isoquinoline-N-oxide (intermediate in Synthesis Example 83b, 50 mg) of agreement are the method described in J. Medisine 84, 35 (1964). The diethyl ether was washed and bent, to give the title (2 mg) somo sristales sastaño slaro. X H-NMR (DMSO-de) d (ppm): 7, 76 (1H, d, J = 6.0 Hz), 6.93 (2H, s ansho), 7.15 (1H, dd, J = 2.0, 8.8 Hz), 7.27 (1H , d, J -2.0 Hz), 7.59 (2H, d, J = 8.8 Hz), 7.63 (1H, d, J = 6.0 Hz), 7.80 (2H, d , J = 8.8 Hz), 9.05 (1H, d, J = 6.0 Hz). ESI-MS: 334.1. Synthesis Example 88b 6- (4-Chloro-bensenosulfonylamino) -1-dimethylaminoisoquinoline l-Sloro-6- (4-sulfosenosulfonylamino) -isoquinoline (Synthesis Example 61b, 60 mg) was dissolved in dimethyl sulfoxide (1 ml), then A methanone-smooth dissociation was added to 50% of dimethylamine (0.04 ml), followed by scaling, stirring at 80 ° C for 10 hours. After cooling it was, water was admissed, followed by extras are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by preparative TLC and solidified using isopropyl ether, to give the title compound (17 mg). XH-NMR (DMSO-de) d (ppm): 2.96 (6H, s), 7.12 (1H, d, J = 6.0 Hz), 7.27 (1H, dd, J = 2, 0, 9.2 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.64 (2H, d, J = 8.8 Hz), 7.85 (2H, d, J = 8.8 Hz), 7.93 (1H, d, J = 6.0 Hz), 8.01 (1H, d, J = 9.2 Hz), 10.91 (1H, S ansho). Synthesis Example 89b 6- (4-Chloro-bensenosulfonylamino) -1-hydroxyisoguinoline 6- (4-Solubensenosulfonylamino) isoguinoline-N-oxide (intermediate in Synthesis Example 83b, 50 mg) was dissolved in anhydrous acetic acid (0.75) ml), followed by heating with agitation at 80 ° C for 16 hours. Then, the mixture was refluxed for 2 hours. After cooling it was, a saturated dissolution of sodium bicarbonate was added, followed by extrasysis are ethyl acetate. The extra was washed is brine and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was dissolved in ethanol (2.0 ml) and water (0.5 ml), followed by heating under reflux for 0.5 hour. After evaporating the solvent, the residue was purified by silica gel solnum, to give the title compound (20 mg) as a red slaro solid. XH-NMR (CDC13) d (ppm): 6.58 (1H, d, J = 7.2 Hz), 7.22 (1H, d, J = 7.2 Hz), 7.31 (1H, dd) , J = 2.0, 8.4 Hz), 7.54 (1H, d, J = 2.0 Hz), 7.56 (2H, d, J = 8.8 Hz), 8.01 (2H , d, J = 8.8 Hz), 8.53 (1H, d, J = 8.4 Hz), 10.36 (1H, s ansho). ESI-MS: 335.1. Synthesis Example 90b 6- (4-Chlorobensenosulfonylamino) -1- ethoxyisoguinoline l-Sloro-6- (4-sulfobensenosulfonylamino) -isoguinoline (Synthesis Example 61b, 57 mg) was dissolved in dimethyl sulfoxide (1 ml). Ethanol (0.1 ml) and 60% sodium hydride (14 mg) were added, followed by scaling, stirring at 80 ° C for 9 hours. After cooling it was, water was adhered to it, followed by extrassion are ethyl acetate. The extra was washed is brine and blended over anhydrous magnesium sulfate. After evaporating the solvent, the residue was purified by preparative TLC and solidified using isopropyl ether, to give the title compound (21 mg). XH-NMR (DMSO-de) d (ppm): 1.38 (3H, t, J = 7.2 Hz), 4.46 (2H, s, J = 7.2 Hz), 7.24 (1H , d, J = 6.0 Hz), 7.35 (1H, dd, J = 2.0, 9.2 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.63 (2H, d, J = 8.8 Hz), 7.90 (1H, d, J = 6.0 Hz), 8.04 (1H, d, J = 9.2 Hz), 10.94 (1H , ansho).
Synthesis Example 91b N- (5-Vinylguinoline-2-yl) -3-pyridine sulfonamide A solution containing 2-amino-5-bromoguinoline (510 mg, Example Prod. Lb), vinyltributyltin (0.94 ml), toluene (4 ml), tetrakistriphenylphosphine palladium (valensia 0) (20 mg) and 2,6-ditersiariobutyl / p-sresol (approximately 0.1 mg) was stirred at 120 ° C for 4 hours. After the reassuring mixture was returned to room temperature, water was adhered to it, followed by extrasysis are ethyl acetate. The ethyl acetate sheet was blended on sodium sulfate and filtered. Then, the resulting solid was washed is hexane, to give 282 mg of a solid which included a vinyl material. The solid was dissolved in 2 ml of pyridine and 412 mg of 3-pyridinesulfonyl sluride was added, followed by agitation at room temperature during noshe. Water was admissed, followed by extrassion are ethyl acetate. The ethyl acetate sheet was blended on sodium sulfate and filtered. Then, the resulting solid was washed with methanol, to give the title suspension (235 mg). XH-NMR (CDC13) d (ppm): 5.59 (1H, dd, J = 10.8 Hz, 1.5 Hz), 5.82 (1H, dd, J = 16.9 Hz, 1.5 Hz), 6.95 (1H, d, J = 10.3 Hz), 7.20 (1H, dd, J = 10.8 Hz, 16.9 Hz), 7.36 (1H, d, J = 8.5 Hz), 7.43 (1H, m), 7.50 (1H, d, J = 8.5 Hz), 7.62 (1H, t, J = 8.5 Hz), 8.24 (1H, d, J = 10.3 Hz), 8.29 (1H, m), 8.74 (1H, m), 9.22 (1H, m). Synthesis Example 92b N- (4-Trifluoromethyl-sulman-7-yl) -4-slorobensenosulfonamide 203 mg (0.96 mmol) of 4-slorobensenosulfonyl sluride was added to a solids pyridine (3 ml) solution having 200 mg ( 0.87 mmol) of 7-amino-4-trifluoromethylsumaine and 1 mg of 4-dimethylaminopyridine, followed by stirring at 70 ° C for 50 minutes. It was given a fuzzy dissolution of 2N slurry, followed by extrasysis are ethyl acetate. Washed the sapa orgánisa are water and brine, was sessed over magnesium sulfate and evaporated. The resulting residue was crystallized from ethyl acetate-diisopropyl ether to give 253 mg of the title compound as a yellow-colored solid. XH-NMR (DMSO-de) d (ppm): 6.87 (1H, s), 7.12 (1H, d, J = 2.4 Hz), 7.17 (1H, dd, J = 2, 6, 8.4 Hz), 7.60 (1H, d, J = 8.4 Hz), 7.67 (2H, d, J = 6.8 Hz), 7.87 (2H, d, J = 6.8 Hz), 11.29 (1H, s).

Claims (23)

  1. CLAIMS 1. 1) An agent for the treatment of arterial sclerosis, psoriasis, Sanser, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anti-coagulant, 3) a suppressor of sanserous metastases or 4) a anti-angiogenic agent based on an inhibitory astivity of integrin expression. 2. 1) The agent for the treatment of arterial sclerosis, psoriasis, Sanser, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anti-coagulant, 3) a suppressor of the sanserous metastases or 4) an anti-angiogenic agent based on an inhibitory astivity of integrin expression, this is claimed in claim 1, where the integrin is integrin a2, a3, a5, a6, av, beta, beta3, beta4, beta5, beta2, a3ßl, a5ßl, adßl, avßl, av 3 or avß5. 3. An inhibitor of integrin expression that is present, is an asthmatic ingredient, a sulfonamide moiety represented by the formula (I), a pharmaceutically aseptable salt thereof or a hydrate thereof
  2. R 'B-K-S02N-Z-R ® in the formula, B represents a C6-C10 aryl ring or a 6 to 10-membered heteroaryl ring which may have a substituent and in the sual a part of the ring may be saturated; K represents a sensible link, -CH = CH- or
  3. (CR4bR5b) mb- (wherein R4b and R5b are the same or different from each other and each one represents a hydrogen atom or a C1-C4 aligyl group, and mb means an integer 1 or 2); R1 represents a hydrogen atom or a C1-C6 alkenyl group; Z represents a senile bond or -CO-NH-; and R represents a ring of ^^ kj jg || II1I..IIÉI i? T? ^ M? C6-C10 aryl or a 6 to 10 membered heteroaryl ring which may have a substituent and in the sual a part of the ring may be saturated, resiliently.
  4. 4. An inhibitor of integrin expression that is present, as an asthmatic ingredient, the sulfonamide somo moiety is claimed in claim 3, a pharmacologically aseptable salt thereof or a hydrate thereof, wherein R is indole, guinyol or isoginoline.
  5. 5. An inhibitor of the integrin expression which is present, is an asthmatic ingredient, a sulfonamide moiety represented by the formula (Ia), a pharmacologically safe salt thereof or a hydrate thereof: in the formula, the ring Aa represents an aromatic, ramosistic, or bisissic ring which may have a substituent; the ring Ba represents an unsaturated 6-membered unsaturated hydrosarbide optionally substituted or a 6-membered unsaturated heterosisol which contains a nitrogen atom somo hetero atom; the Ca ring represents an optionally substituted 5-membered heterosis which contains 1 or 2 nitrogen atoms; RXa represents a hydrogen atom or a C 1 -C 6 alkenyl group; a represents a sensible bond or -CH = CH -, - already represents a sarbono atom or a nitrogen atom; and Za represents -N (R2a) - (where R2a means a hydrogen atom or a lower alkyl group) or a nitrogen atom, respectively.
  6. 6. An inhibitor of the integrin expression that is absorbed, as an asthmatic ingredient, is the sulfonamide somo moiety is claimed in claim 5, a pharmacologically safe salt thereof. or a hydrate of them, where Wa is a sensible cone.
  7. 7. An inhibitor of the integrin expression which is present, as an asthmatic ingredient, the sulphonamide somo moiety is claimed in claim 5, a pharmacologically safe salt thereof or a hydrate thereof, where Wa is a pure linkage; Za is -NH-; and It is already a sarbono atom.
  8. 8. The inhibitor of integrin expression which is present, as an asthmatic ingredient, a sulfonamide somo moiety is claimed in any of claims 5, 6 and 7, a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein the Ba ring is an opsionally substituted bensen or pyridine.
  9. 9. An inhibitor of integrin expression that somprendeis an astivo ingredient, the sulphonamide moiety which is claimed in its following from claims 5 to 8, a farmasologically aseptable salt thereof or a hydrate thereof, wherein the Ca ring is an optionally substituted pyrrole.
  10. 10. An inhibitor of the integrin expression that is present, as an asthmatic ingredient, the sulfonamide somo moiety is claimed in claim 5, a pharmacologically aseptable salt thereof or a hydrate thereof, wherein the Aa ring is a bensen or pyridine. Which can have a substituent; ring B is bensen which may have a substituent; the Ca ring is pyrrole which may have a substitute; Wa is a sensible cone; and Za is -NH-.
  11. 11. An inhibitor of integrin expression which is present, is an asthmatic ingredient, a heterosyisic composition containing sulfonamide represented by the formula (Ib), a pharmaceutically acceptable salt thereof or a hydrate of they : OR in the formula, Ab represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoyl group or also C 1 -C 4 heteroxy which may be substituted are a halogen atom, siane group, - (CO) kbNR 2bR 3b (where R 2b and R3b are the same or different from one another and each one signifies a hydrogen atom or a C1-C4 alkenyl group which may be substituted are a halogen atom, and kb means 0 or 1), an alkenyl or alkenyl group C2-C4 it may have a substituent, or a phenyl or phenoxy group which may have a substituted substituent between the following group A; Bb means an aryl group or monosylate heteroaryl group which may have a substituent selessionate between the following group A, or the following formula: (where the Q ring signifies an aromatic ring that may have one or two nitrogen atoms, and the Mb ring signifies a C5-C12 unsaturated heterosislo or monosislo which has a double bond in somun are the Qb ring; 1 to 4 hetero atoms sequessionados between a nitrogen atom, oxygen atom and sulfur atom, the ring Qb and the ring Mb can have together a nitrogen atom, and the ring Qb and the ring Mb that can have a substituent 1 6 selessionado between the following group A); K signifies a sensible bond or - (CR4bR5b) mb- (where R4 and R5b are the same or different from each other and every one signifies a hydrogen atom or a C1-C4 alkyl group, and mb means an integer 1 or 2), - Tb, b, Xb and Yb are the same or different from each other and say one signifisa = C (Db) - (where Db represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group or alsoxi C1- C4 which may be substituted are a halogen atom, a siane group, - (CO) nbNR6bR7b (where R6 and R7b. Are the same or different from each other and each one signifies a hydrogen atom or a C1-C4 alkyl group which may be substituted are a halogen atom, and nb means 0 or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent, respectively) or a nitrogen atom; Ub and Vb are the same or different from one another and say one means = C (Db) - (where Db has the same meaning given above), nitrogen atom, -CH2-, oxygen atom or -CO-; Zh signifies a sensible bond or -CO-NH-; Rxb means a hydrogen atom or a C1-C4 alkyl group; and ^ -77 means a simple enlase or a double bind; Group A: a halogen atom, a hydroxyl group, an alkyl group or C1-C4 too, which may be substituted are a halogen atom, siane group, -R8bR9bN (NH) pb- (where R8b and R9b are the same or different one of the other, and one signifies a hydrogen atom or a C1-C4 alkyl group which may be substituted are a halogen atom, and pb means 0 or 1, in addition, R8b and R9b may form a 5 or 6 membered ring together. the nitrogen atom to which they are attached, and the ring may also contain a nitrogen atom, oxygen atom or sulfur atom, and may also have a substituent), an aminosulfonyl group which may be substituted are a mono- or di- -C1-C4 alkyl, a C1-C8 asyl group which may have a substituent, a (C1-C4) alkyl group-S (O) sb-C1-C4 alkylene (where sb means an integer between 0, 1 or 2), a phenylsulfonylamino group sual may have a C1-C4 alkyl or a substituent, - (CO) qbNR10bRlxb (where R10b and Rxxb are the same or different from each other and each means a hydrogen atom, or a group C1-C4 alkyl which may be substituted with an amino group which may be substituted with a halogen atom or a C1-C4 alkyl group, and qb means 0 or 1), or an aryl group or heteroaryl group which may have a substituent) .
  12. 12. An inhibitor of integrin expression comprising, as an astivo ingredient, the heterocyclic somatostate which is sulfonamide somo is claimed in claim 11, a pharmaceutically aseptable salt thereof or a hydrate thereof., where Ub and Vb are = C (Db) - (where Db has the same meaning given above) or a nitrogen atom.
  13. 13. An inhibitor of the integrin expression which is present, is an asthmatic ingredient, the heterosysic substance which contains sulfonamide is dissolved in claim 11 or 12, a pharmaceutically acceptable salt thereof or a hydrate thereof, where Zb is an alcohol sensillo
  14. 14. An inhibitor of the expression of integrin which is present, is an astivo ingredient, a heterocyclic substance which is sulfonamide somo is claimed in the following from claims 11 to 13, a pharmaceutically asepable salt thereof or a hydrate thereof, where at least one of Tb, Ub, Vb, b, Xb and Yb is a nitrogen atom.
  15. 15. An inhibitor of the expression of integrin which is present, is an asthmatic ingredient, the heterocyclic substance which contains sulfonamide is claimed in any of the claims 11 to 14, a pharmaceutically acceptable salt thereof or a hydrate thereof, where Ab represents a halogen atom, a C1-C4 alkoyl group or alsoxi group which may be substituted are a halogen atom, siane group, - (C0) rbNRX2bRX3b (where RX2b and RX3b are the same or different one of another and each one represents a hydrogen atom or a C 1 -C 4 alkenyl group which may be substituted are a halogen atom, - and rb signifies 0 or 1) or an alkenyl or C 2 -C 4 alkenyl group which may have an substituent
  16. 16. An inhibitor of integrin expression which is present, is an asthmatic ingredient, the heterocyclic substance which contains sulfonamide is claimed in the following from claims 11 to 15, a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein only one of Tb, Ub, Vb, b, Xb and Yb is a nitrogen atom.
  17. 17. An inhibitor of integrin expression which comprises, as an asthmatic ingredient, the heterocyclic substance which contains sulfonamide is claimed in its claim 11 to 16, a pharmaceutically acceptable salt thereof or a hydrate thereof, wherein only one of Tb, by Yb is a nitrogen atom.
  18. 18. An inhibitor of integrin expression that is present, is an asthmatic ingredient, the sulfonamide moiety which is claimed in its next of claims 5 to 17, a farmasologically aseptable salt thereof or a hydate thereof, wherein the integrin is integrin a2, a3, a5, a6, av, ßl, ß3, ß4 or ß5.
  19. 19. An inhibitor of the integrin expression that is present, is an asthmatic ingredient, the sulphonamide solution which is dispersed at its 5 to 17 ratio, a pharmacologically aseptable salt thereof or a hydrate thereof, where the integrin is integrin a2ßl, a3ßl, a5ßl, a6ßl, avßl, avß3 or avß5.
  20. 20. 1) An agent for the treatment of artery sclerosis, psoriasis, Sanser, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an antisoagulant, 3) a suppressor of the sanserous metastases or 4) an antiangiogenic agent based on to an inhibitory inhibition of integrin expression, which is present, is an active ingredient, The sulfonamide somo moiety is claimed in any of claims 5 to 17, a pharmacologically aseptable salt thereof or a hydrate thereof.
  21. 21. 1) An agent for the treatment of artery sclerosis, psoriasis or osteoporosis or 2) an anti-coagulant based on an inhibitory inhibition of integrin expression, which is present, is an asthmatic ingredient, the sulfonamide somoamide claims, in accordance with claims 5 to 17, a farmasologically aseptable salt thereof or a hydrate thereof.
  22. 22. A method for the prevention, treatment or amelioration of a disease in which there is effective inhibition of integrin expression, by administering a pharmacologically effective dose of the claimed substance in a sublet of claims 3, 5 and 11, a pharmacologically aseptable salt thereof or a hydrate thereof, to a passer.
  23. 23. Use of the claimed compound in its claim 3, 5 and 11, a pharmacologically safe salt of the somatic or a hydrate thereof, to produce an agent for the prevention, treatment or improvement of a disease in which the inhibition is effective. of integrin expression.
MXPA02007249A 2000-02-03 2001-02-01 Integrin expression inhibitors. MXPA02007249A (en)

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US7834049B2 (en) 2010-11-16
CA2399001C (en) 2010-07-20
US20100267754A1 (en) 2010-10-21
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AU2886701A (en) 2001-08-14
CN1396833A (en) 2003-02-12
RU2240826C2 (en) 2004-11-27
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EP1258252A4 (en) 2005-11-02
KR20020073575A (en) 2002-09-27
DE60141889D1 (en) 2010-06-02
HUP0300544A2 (en) 2003-07-28
ES2341843T3 (en) 2010-06-29
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